Inhibitors of glutaminyl cyclase

ABSTRACT

Compounds of formula (I), combinations and uses thereof for disease therapy, 
                         
or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof wherein:
         A represents       

     
       
         
         
             
             
         
       
         
         
           
             and B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and Z are as defined throughout the description and the claims.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. Provisional Application Ser.No. 60/912,528, filed on Apr. 18, 2007, which is incorporated herein byreference in its entirety to the extent permitted by law.

INCORPORATION BY REFERENCE OF SEQUENCE LISTING

The Sequence Listing, which is a part of the present disclosure,includes a computer readable form and a written sequence listingcomprising nucleotide and/or amino acid sequences of the presentinvention. The sequence listing information recorded in computerreadable form is identical to the written sequence listing. The SequenceListing is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The invention relates to novel cyanoguanidine derivatives as inhibitorsof glutaminyl cyclase (QC, EC 2.3.2.5). QC catalyzes the intramolecularcyclization of N-terminal glutamine residues into pyroglutamic acid(5-oxo-prolyl, pGlu*) under liberation of ammonia and the intramolecularcyclization of N-terminal glutamate residues into pyroglutamic acidunder liberation of water.

BACKGROUND OF THE INVENTION

Glutaminyl cyclase (QC, EC 2.3.2.5) catalyzes the intramolecularcyclization of N-terminal glutamine residues into pyroglutamic acid(pGlu*) liberating ammonia. A QC was first isolated by Messer from thelatex of the tropical plant Carica papaya in 1963 (Messer, M. 1963Nature 4874, 1299). 24 years later, a corresponding enzymatic activitywas discovered in animal pituitary (Busby, W. H. J. et al. 1987 J BiolChem 262, 8532-8536; Fischer, W. H. and Spiess, J. 1987 Proc Natl AcadSci USA 84, 3628-3632). For the mammalian QC, the conversion of Gln intopGlu by QC could be shown for the precursors of TRH and GnRH (Busby, W.H. J. et al. 1987 J Biol Chem 262, 8532-8536; Fischer, W. H. and Spiess,J. 1987 Proc Natl Acad Sci USA 84, 3628-3632). In addition, initiallocalization experiments of QC revealed a co-localization with itsputative products of catalysis in bovine pituitary, further improvingthe suggested function in peptide hormone synthesis (Bockers, T. M. etal. 1995 J Neuroendocrinol 7, 445-453). In contrast, the physiologicalfunction of the plant QC is less clear. In the case of the enzyme fromC. papaya, a role in the plant defense against pathogenic microorganismswas suggested (El Moussaoui, A. et a1.2001 Cell Mol Life Sci 58,556-570). Putative QCs from other plants were identified by sequencecomparisons recently (Dahl, S. W. et a1.2000 Protein Expr Purif 20,27-36). The physiological function of these enzymes, however, is stillambiguous. The QCs known from plants and animals show a strictspecificity for L-Glutamine in the N-terminal position of the substratesand their kinetic behavior was found to obey the Michaelis-Mentenequation (Pohl, T. et al. 1991 Proc Natl Acad Sci USA 88, 10059-10063;Consalvo, A. P. et al. 1988 Anal Biochem 175, 131-138; Gololobov, M. Y.et al. 1996 Biol Chem Hoppe Seyler 377, 395-398). A comparison of theprimary structures of the QCs from C. papaya and that of the highlyconserved QC from mammals, however, did not reveal any sequence homology(Dahl, S. W. et al. 2000 Protein Expr Purif 20, 27-36). Whereas theplant QCs appear to belong to a new enzyme family (Dahl, S. W. et al.2000 Protein Expr Purif 20, 27-36), the mammalian QCs were found to havea pronounced sequence homology to bacterial aminopeptidases (Bateman, R.C. et al. 2001 Biochemistry 40, 11246-11250), leading to the conclusionthat the QCs from plants and animals have different evolutionaryorigins.

Recently, it was shown that recombinant human QC as well as QC-activityfrom brain extracts catalyze both, the N-terminal glutaminyl as well asglutamate cyclization. Most striking is the finding, thatcyclase-catalyzed Glu₁-conversion is favored around pH 6.0 whileGln₁-conversion to pGlu-derivatives occurs with a pH-optimum of around8.0. Since the formation of pGlu-A-related peptides can be suppressed byinhibition of recombinant human QC and QC-activity from pig pituitaryextracts, the enzyme QC is a target in drug development for treatment ofAlzheimer's disease.

First inhibitors of QC are described in WO 2004/098625, WO 2004/098591,WO 2005/039548 and WO 2005/075436.

EP 02 011 349.4 discloses polynucleotides encoding insect glutaminylcyclase, as well as polypeptides encoded thereby and their use inmethods of screening for agents that reduce glutaminyl cyclase activity.Such agents are useful as pesticides.

SUMMARY OF THE INVENTION

According to the invention there are provided compounds of formula (I),

or a pharmaceutically acceptable salt, solvate or polymorph thereof,including all tautomers and stereoisomers thereof wherein:R¹ represents alkyl; alkenyl, wherein the double bond is not adjacent tothe nitrogen; carbocyclyl; —C₁₋₆alkyl-carbocyclyl; heterocyclyl;—C₁₋₆alkyl-heterocyclyl; aryl; heteroaryl; —C₁₋₆alkylaryl;—C₁₋₆alkylheteroaryl; -phenyl fused to carbocyclyl or -phenyl fused toheterocyclyl; in which any of the aforesaid carbocyclyl and heterocyclylgroups may optionally be substituted by one or more groups selected frommethyl and oxo;and in which any of the aforesaid phenyl, aryl and heteroaryl groups mayoptionally be substituted by one or more substituents selected fromC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, —C₁₋₆thioalkyl,—SO₂C₁₋₄alkyl, C₁₋₆alkoxy-, —O—C₃₋₈cycloalkyl, C₃₋₈cycloalkyl,—SO₂C₃₋₈cycloalkyl, C₃₋₆alkenyloxy-, C₃₋₆alkynyloxy-, —C(O)C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH₂,—NHC₁₋₄alkyl, —N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl),—C(O)NH₂, —C(O)NH(C₁₋₄alkyl), C(O)OC₁₋₆alkyl, —SOC₁₋₄alkyl and—SOC₃₋₆cycloalkyl;or R¹ represents phenyl substituted by phenyl, or phenyl substituted byan optionally substituted monocyclic heteroaryl group in which any ofthe aforesaid phenyl and monocyclic heteroaryl groups may optionally besubstituted by one or more groups selected from C₁₋₄alkyl, halogen andC₁₋₄alkoxy;or R¹ represents phenyl substituted by benzyloxy- in which any of theaforesaid phenyl or benzyloxy groups may optionally be substituted onthe ring by one or more groups selected from C₁₋₄alkyl, halogen andC₁₋₄alkoxy;andA represents

wherein Y represents a C₂₋₅ alkylene chain, which may optionally besubstituted by one or two methyl groups or may optionally be substitutedby two alkylene substituents at the same position wherein the twoalkylene substituents are joined to each other to form aC₃₋₅-spiro-cycloalkyl group andR², R³ and R⁴ independently represent H or C₁₋₂alkyl, provided that R²and R³ and R⁴ do not all represent H; orA represents

wherein Z represents a bond, —CH₂—, —CH₂—CH₂—, —CH(Me)—, —CH(Me)—CH₂— or—CH₂—CH(Me)— andR⁵ and R⁶ independently represent H or C₁₋₂alkylandB represents H or methyl.

Typically R¹ represents alkyl; alkenyl, wherein the double bond is notadjacent to the nitrogen; carbocyclyl; —C₁₋₆alkyl-carbocyclyl;heterocyclyl; —C₁₋₆alkyl-heterocyclyl; aryl; heteroaryl; —C₁₋₆alkylaryl;—C₁₋₆alkylheteroaryl; -phenyl fused to carbocyclyl or -phenyl fused toheterocyclyl;

in which any of the aforesaid carbocyclyl and heterocyclyl groups mayoptionally be substituted by one or more groups selected from methyl andoxo;

and in which any of the aforesaid phenyl, aryl and heteroaryl groups mayoptionally be substituted by one or more substituents selected fromC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, —C₁₋₆thioalkyl,—SO₂C₁₋₄alkyl, C₁₋₆alkoxy-, —O—C₃₋₈cycloalkyl, C₃₋₈cycloalkyl,—SO₂C₃₋₈cycloalkyl, C₃₋₆alkenyloxy-, C₃₋₆alkynyloxy-, —C(O)C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH₂,—NHC₁₋₄alkyl, —N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl),—C(O)NH₂ and —C(O)NH(C₁₋₄alkyl);or R¹ represents phenyl substituted by phenyl, or phenyl substituted byan optionally substituted monocyclic heteroaryl group in which any ofthe aforesaid phenyl and monocyclic heteroaryl groups may optionally besubstituted by one or more groups selected from C₁₋₄alkyl, halogen andC₁₋₄alkoxy.

Compounds of formula (I) are provided as either the (E) or (Z) isomer atthe double bond substituted by cyano or as a mixture thereof. Thecoverage of the (E) or (Z) isomer or mixture thereof is denoted by

.

Also disclosed are methods of use for the compounds described herein, aswell as processes for their formation.

Other aspects and features will be in part apparent and in part pointedout hereinafter.

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS

Described herein are various compounds that can inhibit activity ofglutaminyl cyclase (QC) and/or QC-like enzymes. Such compounds, andcompositions comprising such, can be used to inhibit QC activity in vivoand for the treatment of conditions effected by modulation of QCactivity. Also described herein are processes for the formation of thesecompounds.

DEFINITIONS

The following definitions and methods are provided to better define thepresent invention and to guide those of ordinary skill in the art in thepractice of the present invention. Unless otherwise noted, terms are tobe understood according to conventional usage by those of ordinary skillin the relevant art.

The terms “k_(i)” or “K_(I)” and “K_(D)” are binding constants, whichdescribe the binding of an inhibitor to and the subsequent release froman enzyme. Another measure is the “IC₅₀” value, which reflects theinhibitor concentration, which at a given substrate concentrationresults in 50% enzyme activity.

The term “DP IV-inhibitor” or “dipeptidyl peptidase IV inhibitor” isgenerally known to a person skilled in the art and means enzymeinhibitors, which inhibit the catalytic activity of DP IV or DP IV-likeenzymes.

“DP IV-activity” is defined as the catalytic activity of dipeptidylpeptidase IV (DP IV) and DP IV-like enzymes. These enzymes arepost-proline (to a lesser extent post-alanine, post-serine orpost-glycine) cleaving serine proteases found in various tissues of thebody of a mammal including kidney, liver, and intestine, where theyremove dipeptides from the N-terminus of biologically active peptideswith a high specificity when proline or alanine form the residues thatare adjacent to the N-terminal amino acid in their sequence.

The term “PEP-inhibitor” or “prolyl endopeptidase inhibitor” isgenerally known to a person skilled in the art and means enzymeinhibitors, which inhibit the catalytic activity of prolyl endopeptidase(PEP, prolyl oligopeptidase, POP).

“PEP-activity” is defined as the catalytic activity of an endoproteasethat is capable to hydrolyze post proline bonds in peptides or proteinswere the proline is in amino acid position 3 or higher counted from theN-terminus of a peptide or protein substrate.

The term “QC” as used herein comprises glutaminyl cyclase (QC) andQC-like enzymes. QC and QC-like enzymes have identical or similarenzymatic activity, further defined as QC activity. In this regard,QC-like enzymes can fundamentally differ in their molecular structurefrom QC. Examples of QC-like enzymes are the glutaminyl-peptidecyclotransferase-like proteins (QPCTLs) from human (GenBankNM_(—)017659), mouse (GenBank BC058181), Macaca fascicularis (GenBankAB168255), Macaca mulatta (GenBank XM_(—)001110995), Canis familiaris(GenBank XM_(—)541552), Rattus norvegicus (GenBank XM_(—)001066591), Musmusculus (GenBank BC058181) and Bos taurus (GenBank BT026254).

The term “QC activity” as used herein is defined as intramolecularcyclization of N-terminal glutamine residues into pyroglutamic acid(pGlu*) or of N-terminal L-homoglutamine or L-β-homoglutamine to acyclic pyro-homoglutamine derivative under liberation of ammonia. Seetherefore schemes 1 and 2.

The term “EC” as used herein comprises the activity of QC and QC-likeenzymes as glutamate cyclase (EC), further defined as EC activity.

The term “EC activity” as used herein is defined as intramolecularcyclization of N-terminal glutamate residues into pyroglutamic acid(pGlu*) by QC. See therefore scheme 3.

The term “QC-inhibitor” “glutaminyl cyclase inhibitor” is generallyknown to a person skilled in the art and means enzyme inhibitors, whichinhibit the catalytic activity of glutaminyl cyclase (QC) or itsglutamyl cyclase (EC) activity.

Potency of QC Inhibition

In light of the correlation with QC inhibition, in preferredembodiments, the subject method and medical use utilize an agent with anIC₅₀ for QC inhibition of 10 μM or less, more preferably of 1 μM orless, even more preferably of 0.1 μM or less or 0.01 μM or less, or mostpreferably 0.001 μM or less. Indeed, inhibitors with K_(i) values in thelower micromolar, preferably the nanomolar and even more preferably thepicomolar range are contemplated. Thus, while the active agents aredescribed herein, for convenience, as “QC inhibitors”, it will beunderstood that such nomenclature is not intending to limit the subjectof the invention to a particular mechanism of action.

Molecular Weight of QC Inhibitors

In general, the QC inhibitors of the subject method or medical use willbe small molecules, e.g., with molecular weights of 500 g/mole or less,400 g/mole or less, preferably of 350 g/mole or less, and even morepreferably of 300 g/mole or less and even of 250 g/mole or less.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanbeing sought by a researcher, veterinarian, medical doctor or otherclinician, which includes alleviation of the symptoms of the disease ordisorder being treated.

As used herein, the term “pharmaceutically acceptable” embraces bothhuman and veterinary use: For example the term “pharmaceuticallyacceptable” embraces a veterinarily acceptable compound or a compoundacceptable in human medicine and health care.

Throughout the description and the claims the expression “alkyl”, unlessspecifically limited, denotes a C₁₋₁₂ alkyl group, suitably a C₁₋₆ alkylgroup, e.g. C₁₋₄ alkyl group. Alkyl groups may be straight chain orbranched. Suitable alkyl groups include, for example, methyl, ethyl,propyl (e.g. n-propyl and isopropyl), butyl (e.g n-butyl, iso-butyl,sec-butyl and tert-butyl), pentyl (e.g. n-pentyl), hexyl (e.g. n-hexyl),heptyl (e.g. n-heptyl) and octyl (e.g. n-octyl). The expression “alk”,for example in the expressions “alkoxy”, “haloalkyl” and “thioalkyl”should be interpreted in accordance with the definition of “alkyl”.Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g.n-propoxy), butoxy (e.g. n-butoxy), pentoxy (e.g. n-pentoxy), hexoxy(e.g. n-hexoxy), heptoxy (e.g. n-heptoxy) and octoxy (e.g. n-octoxy).Exemplary thioalkyl groups include methylthio-. Exemplary haloalkylgroups include fluoroalkyl e.g. CF₃.

The expression “alkenyl”, unless specifically limited, denotes a C₂₋₁₂alkenyl group, suitably a C₂₋₆ alkenyl group, e.g. a C₂₋₄ alkenyl group,which contains at least one double bond at any desired location andwhich does not contain any triple bonds. Alkenyl groups may be straightchain or branched. Exemplary alkenyl groups including one double bondinclude propenyl and butenyl. Exemplary alkenyl groups including twodouble bonds include pentadienyl, e.g. (1E, 3E)-pentadienyl.

The expression “alkynyl”, unless specifically limited, denotes a C₂₋₁₂alkynyl group, suitably a C₂₋₆ alkynyl group, e.g. a C₂₋₄ alkynyl group,which contains at least one triple bond at any desired location and mayor may not also contain one or more double bonds. Alkynyl groups may bestraight chain or branched. Exemplary alkynyl groups include propynyland butynyl.

The expression “alkylene” denotes a chain of formula —(CH₂)_(n)— whereinn is an integer e.g. 2-5, unless specifically limited.

The expression “cycloalkyl”, unless specifically limited, denotes aC₃₋₁₀ cycloalkyl group (i.e. 3 to 10 ring carbon atoms), more suitably aC₃₋₈ cycloalkyl group, e.g. a C₃₋₆ cycloalkyl group. Exemplarycycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl. A most suitable number of ringcarbon atoms is three to six.

The expression “cycloalkenyl”, unless specifically limited, denotes aC₅₋₁₀ cycloalkenyl group (i.e. 5 to 10 ring carbon atoms), more suitablya C₅₋₈ cycloalkenyl group e.g. a C₅₋₆ cycloalkenyl group. Exemplarycycloalkenyl groups include cyclopropenyl, cyclohexenyl, cycloheptenyland cyclooctenyl. A most suitable number of ring carbon atoms is five tosix.

The expression “carbocyclyl”, unless specifically limited, denotes anyring system in which all the ring atoms are carbon and which containsbetween three and twelve ring carbon atoms, suitably between three andten carbon atoms and more suitably between three and eight carbon atoms.Carbocyclyl groups may be saturated or partially unsaturated, but do notinclude aromatic rings. Examples of carbocyclyl groups includemonocyclic, bicyclic, and tricyclic ring systems, in particularmonocyclic and bicyclic ring systems. Other carbocylcyl groups includebridged ring systems (e.g. bicyclo[2.2.1]heptenyl). A specific exampleof a carbocyclyl group is a cycloalkyl group. A further example of acarbocyclyl group is a cycloalkenyl group.

The expression “heterocyclyl”, unless specifically limited, refers to acarbocyclyl group wherein one or more (e.g. 1, 2 or 3) ring atoms arereplaced by heteroatoms selected from N, S and O. A specific example ofa heterocyclyl group is a cycloalkyl group (e.g. cyclopentyl or moreparticularly cyclohexyl) wherein one or more (e.g. 1, 2 or 3,particularly 1 or 2, especially 1) ring atoms are replaced byheteroatoms selected from N, S or O. Exemplary heterocyclyl groupscontaining one hetero atom include pyrrolidine, tetrahydrofuran andpiperidine, and exemplary heterocyclyl groups containing two heteroatoms include morpholine and piperazine. A further specific example of aheterocyclyl group is a cycloalkenyl group (e.g. a cyclohexenyl group)wherein one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1)ring atoms are replaced by heteroatoms selected from N, S and O. Anexample of such a group is dihydropyranyl (e.g.3,4-dihydro-2H-pyran-2-yl-).

The expression “aryl”, unless specifically limited, denotes a C₆₋₁₂ arylgroup, suitably a C₆₋₁₀ aryl group, more suitably a C₆₋₈ aryl group.Aryl groups will contain at least one aromatic ring (e.g. one, two orthree rings). An example of a typical aryl group with one aromatic ringis phenyl. An example of a typical aryl group with two aromatic rings isnaphthyl.

The expression “heteroaryl”, unless specifically limited, denotes anaryl residue, wherein one or more (e.g. 1, 2, 3, or 4, suitably 1, 2 or3) ring atoms are replaced by heteroatoms selected from N, S and O, orelse a 5-membered aromatic ring containing one or more (e.g. 1, 2, 3, or4, suitably 1, 2 or 3) ring atoms selected from N, S and O. Exemplarymonocyclic heteroaryl groups having one heteroatom include: fivemembered rings (e.g. pyrrole, furan, thiophene); and six membered rings(e.g. pyridine, such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl).Exemplary monocyclic heteroaryl groups having two heteroatoms include:five membered rings (e.g. pyrazole, oxazole, isoxazole, thiazole,isothiazole, imidazole, such as imidazol-1-yl, imidazol-2-ylimidazol-4-yl); six membered rings (e.g. pyridazine, pyrimidine,pyrazine). Exemplary monocyclic heteroaryl groups having threeheteroatoms include: 1,2,3-triazole and 1,2,4-triazole. Exemplarymonocyclic heteroaryl groups having four heteroatoms include tetrazole.Exemplary bicyclic heteroaryl groups include: indole (e.g. indol-6-yl),benzofuran, benzthiophene, quinoline, isoquinoline, indazole,benzimidazole, benzthiazole, quinazoline and purine.

The expression “-alkylaryl”, unless specifically limited, denotes anaryl residue which is connected via an alkylene moiety e.g. aC₁₋₄alkylene moiety.

The expression “-alkylheteroaryl”, unless specifically limited, denotesa heteroaryl residue which is connected via an alkylene moiety e.g. aC₁₋₄alkylene moiety.

The term “halogen” or “halo” comprises fluorine (F), chlorine (Cl) andbromine (Br).

The term “amino” refers to the group —NH₂.

The term “phenyl substituted by phenyl” refers to biphenyl.

Stereoisomers:

All possible stereoisomers of the claimed compounds are included in thepresent invention.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.

Preparation and Isolation of Stereoisomers:

Where the processes for the preparation of the compounds according tothe invention give rise to a mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their components enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

Pharmaceutically Acceptable Salts:

In view of the close relationship between the free compounds and thecompounds in the form of their salts or solvates, whenever a compound isreferred to in this context, a corresponding salt, solvate or polymorphis also intended, provided such is possible or appropriate under thecircumstances.

Salts and solvates of the compounds of formula (I) and physiologicallyfunctional derivatives thereof which are suitable for use in medicineare those wherein the counter-ion or associated solvent ispharmaceutically acceptable. However, salts and solvates havingnon-pharmaceutically acceptable counter-ions or associated solvents arewithin the scope of the present invention, for example, for use asintermediates in the preparation of other compounds and theirpharmaceutically acceptable salts and solvates.

Suitable salts according to the invention include those formed with bothorganic and inorganic acids or bases. Pharmaceutically acceptable acidaddition salts include those formed from hydrochloric, hydrobromic,sulfuric, nitric, citric, tartaric, phosphoric, lactic, pyruvic, acetic,trifluoroacetic, triphenylacetic, sulfamic, sulfanilic, succinic,oxalic, fumaric, maleic, malic, mandelic, glutamic, aspartic,oxaloacetic, methanesulfonic, ethanesulfonic, arylsulfonic (for examplep-toluenesulfonic, benzenesulfonic, naphthalenesulfonic ornaphthalenedisulfonic), salicylic, glutaric, gluconic, tricarballylic,cinnamic, substituted cinnamic (for example, phenyl, methyl, methoxy orhalo substituted cinnamic, including 4-methyl and 4-methoxycinnamicacid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or3-hydroxy-2-naphthoic), naphthaleneacrylic (for examplenaphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2- or4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic (forexample 1,4-benzenediacrylic), isethionic acids, perchloric, propionic,glycolic, hydroxyethanesulfonic, pamoic, cyclohexanesulfamic, salicylic,saccharinic and trifluoroacetic acid. Pharmaceutically acceptable basesalts include ammonium salts, alkali metal salts such as those of sodiumand potassium, alkaline earth metal salts such as those of calcium andmagnesium and salts with organic bases such as dicyclohexylamine andN-methyl-D-glucamine.

All pharmaceutically acceptable acid addition salt forms of thecompounds of the present invention are intended to be embraced by thescope of this invention.

Polymorph Crystal Forms:

Furthermore, some of the crystalline forms of the compounds may exist aspolymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e. hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention. Thecompounds, including their salts, can also be obtained in the form oftheir hydrates, or include other solvents used for theircrystallization.

Prodrugs:

The present invention further includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the desired therapeutically active compound. Thus, in thesecases, the methods of treatment of the present invention, the term“administering” shall encompass the treatment of the various disordersdescribed with prodrug versions of one or more of the claimed compounds,but which converts to the above specified compound in vivo afteradministration to the subject. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Protective Groups:

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991, fully incorporatedherein by reference. The protecting groups may be removed at aconvenient subsequent stage using methods known from the art.

As used herein, the term “composition” is intended to encompass aproduct comprising the claimed compounds in the therapeuticallyeffective amounts, as well as any product which results, directly orindirectly, from combinations of the claimed compounds.

Carriers and Additives for Galenic Formulations:

Thus, for liquid oral preparations, such as for example, suspensions,elixirs and solutions, suitable carriers and additives mayadvantageously include water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like; for solid oral preparationssuch as, for example, powders, capsules, gelcaps and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like.

Carriers, which can be added to the mixture, include necessary and inertpharmaceutical excipients, including, but not limited to, suitablebinders, suspending agents, lubricants, flavorants, sweeteners,preservatives, coatings, disintegrating agents, dyes and coloringagents.

Soluble polymers as targetable drug carriers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamide-phenol, or polyethyleneoxidepolyllysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example, polyacticacid, polyepsilon caprolactone, polyhydroxy butyeric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Suitable binders include, without limitation, starch, gelatin, naturalsugars such as glucose or betalactose, corn sweeteners, natural andsynthetic gums such as acacia, tragacanth or sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like.

Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

Compounds

When carbocyclyl and heterocyclyl are substituted, they are typicallysubstituted by 1 or 2 substituents (e.g. 1 substituent). Typically thesubstituent is methyl. More typically carbocyclyl and heterocyclylgroups are unsubstituted.

When aryl and heteroaryl are substituted, they are typically substitutedby 1, 2 or 3 (e.g. 1 or 2) substituents. Substituents for aryl andheteroaryl are selected from C₁₋₆alkyl (e.g. methyl), C₂₋₆alkenyl (e.g.buten-3-yl), C₂₋₆alkynyl (e.g. butyn-3-yl), C₁₋₆haloalkyl (e.g.fluoromethyl, trifluoromethyl), —C₁₋₆thioalkyl (e.g. —S-methyl),—SO₂C₁₋₄alkyl (e.g. —SO₂-methyl), C₁₋₆alkoxy- (e.g. methoxy, ethoxy),—O—C₃₋₈cycloalkyl (e.g. —O-cyclopentyl), C₃₋₈cycloalkyl (e.g.cyclopropyl, cyclohexyl), —SO₂C₃₋₈cycloalkyl (e.g. —SO₂cyclohexyl),C₃₋₆alkenyloxy- (e.g. —O-buten-2-yl), C₃₋₆alkynyloxy- (e.g.—O-buten-2-yl), —C(O)C₁₋₆alkyl (e.g. —C(O)ethyl), —C(O)OC₁₋₆alkyl (e.g.—C(O)O-methyl), C₁₋₆alkoxy-C₁₋₆alkyl- (e.g. methoxy-ethyl-), nitro,halogen (e.g. fluoro, chloro, bromo), cyano, hydroxyl, —C(O)OH, —NH₂,—NHC₁₋₄alkyl (e.g. —NHmethyl), —N(C₁₋₄alkyl)(C₁₋₄alkyl) (e.g.—N(methyl)₂), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl) (e.g. —C(O)N(methyl)₂),—C(O)NH₂ and —C(O)NH(C₁₋₄alkyl) (e.g. —C(O)NHmethyl). Further suitableexamples are —C(O)OC₁₋₆alkyl (e.g. C(O)OMe), —SOC₁₋₄alkyl (e.g. SOMe)and —SOC₃₋₆cycloalkyl (e.g. —SO-cyclopropyl). More typically,substituents will be selected from C₁₋₆alkyl (e.g. methyl),C₁₋₆haloalkyl (e.g. C₁₋₆-fluoroalkyl, e.g. CF₃), C₁₋₆alkoxy (e.g. OMe),halogen, hydroxy and cyano. Most typically, substituents will beselected from C₁₋₆alkyl (e.g. methyl), C₁₋₆haloalkyl (e.g.C₁₋₆-fluoroalkyl, e.g. CF₃), C₁₋₆alkoxy (e.g. OMe), halogen and hydroxy.

When R¹ represents alkyl, examples include propyl (e.g. n-propyl,isopropyl), butyl (e.g. n-butyl-sec-butyl, isobutyl and tert-butyl),pentyl (e.g. n-pentyl, 3,3,-dimethylpropyl), hexyl, heptyl and octyl.

When R¹ represents alkenyl, examples include propen-2-yl (i.e.—CH₂—CH═CH₂), buten-2-yl, buten-3-yl and penten-3-yl.

When R¹ represents carbocyclyl (which may optionally be substituted),examples include cycloalkyl and cycloalkenyl. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl. Examples of cycloalkenyl include cyclohexenyl (e.g.cyclohex-2-enyl, cyclohex-3-enyl). Examples of substituted carbocyclylinclude 2-methyl-cyclohexyl-, 3-methyl-cyclohexyl-,4-methyl-cyclohexyl-, 2-methyl-cyclohex-2-enyl,2-methyl-cyclohex-3-enyl, 3-methyl-cyclohex-3-enyl,3-methyl-cyclohex-3-enyl.

When R¹ represents —C₁₋₆alkyl-carbocyclyl (which may optionally besubstituted), examples include -methyl-cyclopentyl, -methyl-cyclohexyl,-ethyl-cyclohexyl, -propyl-cyclohexyl, -methyl-cyclohexenyl,-ethyl-cyclohexenyl, -methyl(4-methylcyclohexyl) and -propyl(3-methylcyclyohexyl).

When R¹ represents heterocyclyl (which may optionally be substituted),examples include tetrahydrofuranyl, morpholinyl, piperidinyl,3,4-dihydro-2H-pyranyl, pyrrolidinyl, methyltetrahydrofuranyl- (e.g.5-methyltetrahydrofuran-2-yl).

When R¹ represents —C₁₋₆alkyl-heterocyclyl (which may optionally besubstituted), examples include -methyl-tetrahydrofuranyl (e.g.-methyl-tetrahydrofuran-2-yl, -methyl-tetrahydrofuran-3-yl),-ethyl-tetrahydrofuranyl, -methyl-piperidinyl.

When R¹ represents optionally substituted aryl, aryl may typicallyrepresent phenyl. Aryl may most typically represent substituted phenyl.Exemplary substituted phenyl groups include 2,4-dichlorophenyl-,2,4-difluororophenyl-, 2,4-dimethoxyphenyl-,2,4-dimethylphenyl-2,4-bis(trifluoromethyl)phenyl-,2,4,6-trifluorophenyl-, 2,4,6-trimethylphenyl-, 2,6-dichlorophenyl-,2,6-difluorophenyl-, 2,6-dimethoxyphenyl-, 2-isopropyl-6-methylphenyl-,3-(cyclopentyloxy)-4-methoxyphenyl-, 3,4,5-trimethoxyphenyl-,3,4-dimethoxyphenyl-, 3,4-dichlorophenyl-, 3,4-dimethylphenyl-,3,4,5-trifluorophenyl-, 3,5-bis(trifluororomethyl)phenyl-,3,5-dimethoxyphenyl-, 3-methoxyphenyl-, 4-(trifluoromethyl)phenyl-,4-bromo-2-(trifluoromethyl)phenyl-, 4-bromophenyl-,4-chloro-3-(trifluoromethyl)phenyl-, 4-chlorophenyl-, 4-cyanophenyl-,4-ethoxyphenyl-, 4-ethylphenyl-, 4-fluorophenyl-, 4-isopropylphenyl-,4-methoxyphenyl-. Alternatively, R¹ may represents unsubstitutedphenyl-.

When R¹ represents optionally substituted aryl and aryl representsnaphthyl, examples include unsubstituted naphthyl (e.g. naphthalen-1-yl,naphthalen-2-yl, naphthalen-3-yl) as well as substituted naphthyl (e.g.4-methyl-naphthalen-2-yl-, 5-methyl-naphthalen-3-yl-,7-methyl-naphthalen-3-y- and 4-fluoro-naphthalen-2-yl-).

When R¹ represents optionally substituted heteroaryl, examples includemonocyclic rings (e.g. 5 or 6 membered rings) and bicyclic rings (e.g. 9or 10 membered rings) which may optionally be substituted. Example 5membered rings include pyrrolyl (e.g. pyrrol-2-yl) and imidazolyl (e.g.1H-imidazol-2-yl or 1H-imidazol-4-yl), pyrazolyl (e.g. 1H-pyrazol-3-yl),furanyl (e.g. furan-2-yl), thiazolyl (e.g. thiazol-2-yl), thiophenyl(e.g. thiophen-2-yl, thiophen-3-yl). Example 6 membered rings includepyridinyl (e.g. pyridine-2-yl and pyridine-4-yl). Specific substituentsthat may be mentioned are one or more e.g. 1, 2 or 3 groups selectedfrom halogen, hydroxyl, alkyl (e.g. methyl) and alkoxy- (e.g. methoxy-).Example substituted 5 membered rings include 4,5-dimethyl-furan-2-yl-,5-hydroxymethyl-furan-2-yl-, 5-methyl-furan-2-yl- and6-methyl-pyridin-2-yl-. An example substituted 6-membered ring is1-oxy-pyridin-4-yl-. Example 9 membered rings include 1H indolyl (e.g.1H-indol-3-yl, 1H-indol-5-yl), benzothiophenyl (e.g.benzo[b]thiophen-3-yl, particularly 2-benzo[b]thiophen-3-yl),benzo[1,2,5]-oxadiazolyl (e.g. benzo[1,2,5]-oxadiazol-5-yl),benzo[1,2,5]-thiadiazolyl (e.g. benzo[1,2,5]-thiadiazol-5-yl). Example10 membered rings include quinolinyl (e.g. quinolin-3-yl, quinolin-4-yl,quinolin-8-yl). Specific substituents that may be mentioned are one ormore e.g. 1, 2 or 3 groups selected from halogen, hydroxyl, alkyl (e.g.methyl) and alkoxy- (e.g. methoxy-). Example substituted 9-memberedrings include 1-methyl-1H-indol-3-yl, 2-methyl-1H-indol-3-yl,6-methyl-1H-indol-3-yl. Example substituted 10 membered rings include2-chloro-quinolin-3-yl, 8-hydroxy-quinolin-2-yl, oxo-chromenyl (e.g.4-oxo-4H-chromen-3-yl) and 6-methyl-4-oxo-4H-chromen-3-yl.

When R¹ represents -alkylaryl in which aryl is optionally substituted,examples include —C₁₋₄alkylaryl. Another specific group is-alkyl(substituted phenyl) e.g. in which phenyl is substituted by one ormore groups selected from alkyl, fluoroalkyl, halogen and alkoxy (e.g.methyl, trifluoromethyl, tert-butyl, chloro, fluoro and methoxy) and,for example, alkyl is C₁₋₄ alkyl. Another specific group is-alkyl(bicyclic aryl) e.g. wherein bicyclic aryl is optionallysubstituted naphthyl. A further specific group is benzyl.

When R¹ represents -alkylheteroaryl in which heteroaryl is optionallysubstituted, examples include —C₁₋₄alkylheteroaryl e.g.-methylheteroaryl and -ethylheteroaryl (e.g. 1-heteroarylethyl- and2-heteroarylethyl-), -propylheteroaryl and -butylheteroaryl in whichheteroaryl is optionally substituted. Specific examples of-alkylheteroaryl groups include pyridinylmethyl-,N-methyl-pyrrol-2-methyl-N-methyl-pyrrol-2-ethyl-,N-methyl-pyrrol-3-methyl-, N-methyl-pyrrol-3-ethyl-,2-methyl-pyrrol-1-methyl-, 2-methyl-pyrrol-1-ethyl-,3-methyl-pyrrol-1-methyl-, 3-methyl-pyrrol-1-ethyl-, 4-pyridino-methyl-,4-pyridino-ethyl-, 2-(thiazol-2-yl)-ethyl-, 2-ethyl-indol-1-methyl-,2-ethyl-indol-1-ethyl-, 3-ethyl-indol-1-methyl-, 3-ethyl-indol-1-ethyl-,4-methyl-pyridin-2-methyl-, 4-methyl-pyridin-2-yl-ethyl-,4-methyl-pyridin-3-methyl-, 4-methyl-pyridin-3-ethyl-.

When R¹ represents optionally substituted -phenyl fused to optionallysubstituted carbocyclyl, examples include indanyl (e.g. indan-4-yl-,2-methyl-indan-4-yl-), indenyl and tetralinyl.

When R¹ represents optionally substituted -phenyl fused to optionallysubstituted heterocyclyl, examples include benzo[1,3]dioxo-4-yl- and2,3-dihydro-benzo[1,4]dioxin-4-yl-.

When R¹ represents phenyl substituted by phenyl, or phenyl substitutedby a monocyclic heteroaryl group, in which any of aforesaid phenyl andheteroaryl groups may optionally be substituted, typically the phenylring connected directly to the nitrogen atom is unsubstituted and theterminal phenyl ring or the monocyclic heteroaryl ring is optionallysubstituted by one, two or three substitutents (e.g. one or two, e.g.one). Typically the terminal phenyl or monocyclic heteroaryl group isunsubstituted. Typically the terminal phenyl or monocyclic heteroarylgroup substitutes the other phenyl group at the 4-position. Examplesinclude -biphenyl-4-yl and 4-(oxazol-5-yl)phenyl-.

When R¹ represents phenyl substituted by benzyloxy- in which any of theaforesaid phenyl or benzyloxy groups may optionally be substituted onthe ring by one or more groups selected from C₁₋₄alkyl, halogen andC₁₋₄alkoxy, examples include 4-(benzyloxy)phenyl-. Further examplesinclude 4-((4-fluoro-benzyl)oxy)phenyl-, 4-((4-chloro-benzyl)oxy)phenyl-and 4-((4-methoxy-benzyl)oxy)phenyl-. Typically the terminal benzyloxygroup substitutes the phenyl group at the 4-position. Typically thephenyl ring connected directly to the nitrogen atom is unsubstituted.

When A represents

Examples of R² include H, methyl and ethyl.

Examples of R³ include H, methyl and ethyl.

Examples of R⁴ include H, methyl and ethyl.

Examples of group Y include —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—,—CH₂CH(Me)CH₂—, —CH₂CH(Me)CH₂CH₂—, —CH₂CH₂CH(Me)CH₂— and

wherein the imidazole ring is on the left hand side

When A represents

Examples of R⁵ include H, methyl and ethyl.

Examples of R⁶ include H, methyl and ethyl.

Suitably R¹ represents alkyl, aryl; carbocyclyl; heteroaryl; -phenylfused to carbocyclyl; phenyl fused to heterocyclyl;

or R¹ represents phenyl substituted by optionally substituted phenyl orphenyl substituted by a monocyclic heteroaryl group; any of whichaforesaid aryl, carbocyclyl, heteroaryl, phenyl and heterocyclyl mayoptionally be substituted.

When R¹ represents optionally substituted aryl, R¹ suitably representsoptionally substituted phenyl, especially substituted phenyl. Examplesubstituents are selected from C₁₋₆alkyl (e.g. methyl, ethyl,isopropyl), C₁₋₆alkoxy (e.g. methoxy), —O—C₃₋₈cycloalkyl (e.g.—O-cyclopentyl), C₁₋₆haloalkyl (e.g. trifluoromethyl) and halogen (e.g.chloro).

More suitably R¹ represents aryl; heteroaryl; -phenyl fused tocarbocyclyl; phenyl fused to monocyclic heterocyclyl;

or R¹ represents phenyl substituted by phenyl, or phenyl substituted bya monocyclic heteroaryl group; in which any of the aforesaid phenyl,heteroaryl, carbocyclyl and heterocyclyl may optionally be substituted.

In one embodiment R¹ represents optionally substituted aryl. In anotherembodiment R¹ represents optionally substituted heteroaryl. In a thirdembodiment R¹ represents optionally substituted phenyl fused tooptionally substituted carbocyclyl. In another embodiment R¹ representsoptionally substituted phenyl fused to optionally substitutedheterocyclyl. In a further embodiment R¹ represents optionallysubstituted phenyl substituted by optionally substituted phenyl oroptionally substituted phenyl substituted by an optionally substitutedmonocyclic heteroaryl group.

When R¹ represents optionally substituted aryl, R¹ suitably representsoptionally substituted phenyl, especially substituted phenyl.

When R¹ represents substituted phenyl, phenyl suitably has one, two orthree substituents (e.g. one or two substituents, e.g. one substituent,e.g. one substituent). When phenyl has three substituents, thesubstituents are for example at the 2, 4 and 6 positions of the phenylring or alternatively at the 3, 4, and 5 positions of the phenyl ring.When phenyl has two substituents, the substituents are for example atthe 3 and 4 positions of the phenyl ring or at the 3 and 5 positions ofthe phenyl ring. When phenyl has one substituent, the substituent is atthe 2, 3 or 4 position of the phenyl ring, most suitably at the4-position of the phenyl ring.

Example substituents are selected from C₁₋₆alkyl (e.g. methyl, ethyl,isopropyl), C₁₋₆alkoxy (e.g. methoxy), C₁₋₆haloalkyl (e.g.trifluoromethyl) and halogen (e.g. chloro). Another example substituentis cyano. Further example substituents are selected from C₁₋₃alkyl (e.g.methyl, ethyl, isopropyl), C₁₋₃alkoxy (e.g. methoxy), C₁₋₃haloalkyl(e.g. trifluoromethyl), halogen (e.g. chloro) and cyano. Specificexamples include 2,4,6-trimethylphenyl-, 3,4,5-trimethoxyphenyl-,3,4-dichlorophenyl-, 3,4-dimethylphenyl-, 3,5-dimethoxyphenyl-,4-methoxyphenyl-, 4-cyanophenyl-, 4-ethoxyphenyl-, 4-ethylphenyl-,4-isopropylphenyl- or 4-methoxyphenyl-.

When R¹ represents unsubstituted aryl, R¹ suitably represents phenyl,naphthalen-1-yl or naphthalen-2-yl.

When R¹ represents optionally substituted heteroaryl, R¹ suitablyrepresents benzo[c][1,2,5]thiadiazol-6-yl.

When R¹ represents optionally substituted phenyl fused to optionallysubstituted heterocyclyl, R¹ suitably represents2,3-dihydrobenzo[b][1,4]dioxin-7-yl or benzo[d][1,3]dioxol-6-yl.

When R¹ represents phenyl substituted by phenyl, or phenyl substitutedby a monocyclic heteroaryl group in which any of aforesaid phenyl and/ormonocyclic heteroaryl may optionally be substituted. R¹ suitablyrepresents biphenyl-4-yl.

More suitably R¹ represents aryl; heteroaryl; phenyl fused toheterocyclyl;

or R¹ represents phenyl substituted by phenyl, or phenyl substituted bya monocyclic heteroaryl group in which any of the aforementioned phenyl,aryl, heteroaryl and heterocyclyl may optionally be substituted.

Most suitably R¹ represents substituted phenyl or R¹ represents phenylfused to heterocyclyl.

Most suitably R¹ represents substituted phenyl. Alternatively, mostsuitably R¹ represents phenyl fused to heterocyclyl.

Suitably A represents

R² suitably represents H.

R³ suitably represents H or methyl.

R⁴ suitably represents H or methyl.

In one embodiment of the invention, R³ represents H and R⁴ representsmethyl. In another embodiment, R³ represents methyl and R⁴ represents H.

Most suitably R² represents H. R³ represents H and R⁴ represents methyl.

Suitably Y represents an unsubstituted C₂₋₅ alkylene chain. Moresuitably Y represents —(CH₂)₃— or —(CH₂)₄—. In one embodiment, Yrepresents —(CH₂)₃—. In another embodiment, Y represents —(CH₂)₄—.

When Y represents a C₂₋₅ alkylene chain, which is substituted by twoalkylene substituents at the same position wherein the two alkylenesubstituents are joined to each other to form a C₃₋₅-spiro-cycloalkylgroup, the spiro-cycloalkyl group is suitably C₃-spiro-cycloalkyl.

Alternatively A represents

In one embodiment R⁵ represents H and R⁵ represents H. In anotherembodiment R⁵ represents H and R⁶ represents C₁₋₂alkyl. In a thirdembodiment R⁵ represents C₁₋₂alkyl and R⁶ represents H.

Suitably Z represents a bond, —CH₂— or —CH₂CH₂—. In one embodiment Zrepresents a bond. In another embodiment, Z represents —CH₂—. In a thirdembodiment, Z represents —CH₂CH₂—.

More suitably A represents

Most suitably A represents

B suitably represents H.

When benzimidazolyl is shown as benzimidazol-5-yl, which is representedas:

the person skilled in the art will appreciate that benzimidazol-6-yl,which is represented as:

is an equivalent structure. As employed herein, the two forms ofbenzimidazolyl are covered by the term “benzimidazol-5-yl”.Processes

A process for preparation of a compound of formula (I)

wherein R¹, A and B are defined as above.comprises reaction of a compound of formula (II)

with a compound of formula (III).

The reaction is typically performed in the presence of a reagent thatremoves hydrogen disulfide (e.g. a carbodiimide such asN¹-((ethylimino)methylen)-N³,N³-dimethylpropan-1,3-diaminehydrochloride).

The reaction may be carried out in a polar organic solvent or a mixturethereof (e.g. a mixture of ethanol and dimethylformamide).

A compound of formula (II) may be prepared by reaction of a compound offormula (IV)

wherein M⁺ represents a metal ion (e.g. sodium ion, Na⁺)with a compound of formula (V)

The reaction may suitably be carried out in a polar protic organicsolvent (e.g. an alcohol such as ethanol) at elevated temperature.

Compounds of formulae (III). (IV) and (V) are either known or may beprepared by conventional methods known per se.

Alternatively a compound of formula (I) may be prepared by reaction of acompound of formula (VI)

wherein R⁷ represents C₁₋₆alkyl e.g. methylwith a compound of formula (III).

The reaction may suitably be carried out in a polar protic organicsolvent (e.g. an alcohol such as ethanol) at elevated temperature.

A compound of formula (VI) may be prepared by reaction of a compound offormula (VII)

wherein R⁸ represents C₁₋₆alkyl e.g. methylwith a compound of formula (VIII)H₂N—R¹  (VIII)The reaction may suitably be carried out in a polar protic organicsolvent (e.g. an alcohol such as ethanol) at elevated temperature.

Compounds of formula (VI) may be formed in situ i.e. the compounds offormula (VI) need not be isolated from the reaction mixture afterreaction of compounds of formula (VII) and (VII) before onwards reactionto compounds of formula (I).

Compounds of formulae (III), (VII) and (VII) are either known or may beprepared by conventional methods known per se. See for example Buchholzet al, J. Med. Chem., 2006, 49(2), p 664-677.

For example, when A represents

wherein R², R³, R⁴ and Y are defined as above and B represents H, acompound of formula (IIIa)

may be prepared from a compound of formula (IX)

by cleavage of the isoindolin-1,3-dione group (e.g. by use ofhydrazine).

A compound of formula (IX) may be prepared by deprotection of a compoundof formula (X)

wherein PG represents a protecting group (e.g. trityl) and L⁻ representsa suitable counterion such as Br⁻. (Suitable deprotecting conditionsinclude use of trifluoroacetic acid when PG represents trityl).

A compound of formula (X) may be prepared by reaction of a compound offormula (XI)

with a compound of formula (XII)

wherein L represents a suitable leaving group e.g. Br.

The reaction may typically be carried out at elevated temperature in anorganic solvent (e.g. acetonitrile).

A compound of formula (XI) may be prepared from a compound of formula(XIII)

in the presence of a base (e.g. triethylamine) and a suitable protectingreagent (e.g. chlorotriphenylmethane) in a polar organic solvent (e.g.dimethylformamide).

Compounds of formula (XII) and (XIII) are either known or may beprepared by conventional methods known per se.

Therapeutic Uses

Physiological substrates of QC (EC) in mammals are, e.g. amyloidbeta-peptides (3-40), (3-42), (11-40 and (11-42), ABri, ADan, Gastrin,Neurotensin, FPP, CCL 2, CCL 7, CCL 8, CCL 16, CCL 18, Fractalkine,Orexin A, [Gln³]-glucagon(3-29), [Gln⁵]-substance P(5-11) and thepeptide QYNAD. For further details see table 1. The compounds and/orcombinations according to the present invention and pharmaceuticalcompositions comprising at least one inhibitor of QC (EC) are useful forthe treatment of conditions that can be treated by modulation of QCactivity.

TABLE 1 Amino acid sequences of physiological active peptides with anN-terminal glutamine residue, which are prone to be cyclized to finalpGlu Peptide Amino acid sequence Function Abeta(1-42)Asp-Ala-Glu-Phe-Arg-His-Asp-Ser- Plays a role in (SEQ ID NO: 1)Gly-Tyr-Glu-Val-His-His-Gln-Lys- neurodegeneration, e.g. inLeu-Val-Phe-Phe-Ala-Glu-Asp-Val- Alzheimer's Disease, FamilialGly-Ser-Asn-Lys-Gly-Ala-Ile-Ile- British Dementia, FamilialGly-Leu-Met-Val-Gly-Gly-Val-Val- Danish Dementia, Down Ile-Ala SyndromeAbeta(1-40) Asp-Ala-Glu-Phe-Arg-His-Asp-Ser- Plays a role in (SEQ ID NO:2) Gly-Tyr-Glu-Val-His-His-Gln-Lys- neurodegeneration, e.g. inLeu-Val-Phe-Phe-Ala-Glu-Asp-Val- Alzheimer's Disease, FamilialGly-Ser-Asn-Lys-Gly-Ala-Ile-Ile- British Dementia, FamilialGly-Leu-Met-Val-Gly-Gly-Val-Val Danish Dementia, Down SyndromeAbeta(3-42) Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr- Plays a role in (SEQ ID NO:3) Glu-Val-His-His-Gln-Lys-Leu-Val- neurodegeneration, e.g. inPhe-Phe-Ala-Glu-Asp-Val-Gly-Ser- Alzheimer's Disease, FamilialAsn-Lys-Gly-Ala-Ile-Ile-Gly-Leu- British Dementia, FamilialMet-Val-Gly-Gly-Val-Val-Ile-Ala Danish Dementia, Down SyndromeAbeta(3-40) Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr- Plays a role in (SEQ ID NO:4) Glu-Val-His-His-Gln-Lys-Leu-Val- neurodegeneration, e.g. inPhe-Phe-Ala-Glu-Asp-Val-Gly-Ser- Alzheimer's Disease, FamilialAsn-Lys-Gly-Ala-Ile-Ile-Gly-Leu- British Dementia, FamilialMet-Val-Gly-Gly-Val-Val Danish Dementia, Down Syndrome Abeta(11-42)Glu-Val-His-His-Gln-Lys-Leu-Val- Plays a role in (SEQ ID NO: 16)Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser- neurodegeneration, e.g. inAsn-Lys-Gly-Ala-Ile-Ile-Gly-Leu- Alzheimer's Disease, FamilialMet-Val-Gly-Gly-Val-Val-Ile-Ala British Dementia, Familial DanishDementia, Down Syndrome Abeta(11-40) Glu-Val-His-His-Gln-Lys-Leu-Val-Plays a role in (SEQ ID NO: 17) Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser-neurodegeneration, e.g. in Asn-Lys-Gly-Ala-Ile-Ile-Gly-Leu- Alzheimer'sDisease, Familial Met-Val-Gly-Gly-Val-Val British Dementia, FamilialDanish Dementia, Down Syndrome ABri EASNCFA IRHFENKFAV ETLICPyroglutamated form plays a (SEQ ID NO: 18) SRTVKKNIIEEN role inFamilial British Dementia ADan EASNCFA IRHFENKFAV ETLIC Pyroglutamatedform plays a (SEQ ID NO: 19) FNLFLNSQEKHY role in Familial DanishDementia Gastrin 17 QGPWL EEEEEAYGWM DF Gastrin stimulates the stomachSwiss-Prot: P01350 (amide) mucosa to produce and secrete (SEQ ID NO: 5)hydrochloric acid and the pancreas to secrete its digestive enzymes. Italso stimulates smooth muscle contraction and increases bloodcirculation and water secretion in the stomach and intestine.Neurotensin QLYENKPRRP YIL Neurotensin plays an endocrine Swiss-Prot:P30990 or paracrine role in the (SEQ ID NO: 6) regulation of fatmetabolism. It causes contraction of smooth muscle. FPP QEP amide Atripeptide related to thyrotrophin releasing hormone (TRH), is found inseminal plasma. Recent evidence obtained in vitro and in vivo showedthat FPP plays an important role in regulating sperm fertility. TRH QHPamide TRH functions as a regulator of Swiss-Prot: P20396 thebiosynthesis of TSH in the anterior pituitary gland and as aneurotransmitter/ neuromodulator in the central and peripheral nervoussystems. GnRH QHWSYGL RP(G) amide Stimulates the secretion ofSwiss-Prot: P01148 gonadotropins; it stimulates the (SEQ ID NO: 7)secretion of both luteinizing and follicle-stimulating hormones. CCL16(small QPKVPEW VNTPSTCCLK Shows chemotactic activity for induciblecytokine YYEKVLPRRL VVGYRKALNC lymphocytes and monocytes A16) HLPAIIFVTKRNREVCTNPN but not neutrophils. Also shows Swiss-Prot: O15467 DDWVQEYIKDPNLPLLPTRN potent myelosuppressive (SEQ ID NO: 8) LSTVKIITAK NGQPQLLNSQactivity, suppresses proliferation of myeloid progenitor cells.Recombinant SCYA16 shows chemotactic activity for monocytes and THP-1monocytes, but not for resting lymphocytes and neutrophils. Induces acalcium flux in THP-1 cells that were desensitized by prior expressionto RANTES. CCL8 (small QPDSVSI PITCCFNVIN Chemotactic factor thatattracts inducible cytokine RKIPIQRLES YTRITNIQCP monocytes,lymphocytes, A8) KEAVIFKTKR GKEVCADPKE basophils and eosinophils. MaySwiss-Prot: P80075 RWVRDSMKHL DQIFQNLKP play a role in neoplasia and(SEQ ID NO: 9) inflammatory host responses. This protein can bindheparin. CCL2 (MCP-1, small QPDAINA PVTCCYNFTN Chemotactic factor thatattracts inducible cytokine RKISVQRLAS YRRITSSKCP monocytes andbasophils but A2) KEAVIFKTIV AKEICADPKQ not neutrophils or eosinophils.Swiss-Prot: P13500 KWVQDSMDHL DKQTQTPKT Augments monocyte anti-tumor(SEQ ID NO: 10) activity. Has been implicated in the pathogenesis ofdiseases characterized by monocytic infiltrates, like psoriasis,rheumatoid arthritis or atherosclerosis. May be involved in therecruitment of monocytes into the arterial wall during the diseaseprocess of atherosclerosis. Binds to CCR2 and CCR4. CCL18 (smallQVGTNKELC CLVYTSWQIP Chemotactic factor that attracts inducible cytokineQKFIVDYSET SPQCPKPGVI lymphocytes but not monocytes A18) LLTKRGRQICADPNKKWVQK or granulocytes. May be Swiss-Prot: P55774 YISDLKLNA involvedin B cell migration into (SEQ ID NO: 11) B cell follicles in lymphnodes. Attracts naive T lymphocytes toward dendritic cells and activatedmacrophages in lymph nodes, has chemotactic activity for naive T cells,CD4+ and CD8+ T cells and thus may play a role in both humoral andcell-mediated immunity responses. Fractalkine QHHGVT KCNITCSKMT Thesoluble form is chemotactic (neurotactin) SKIPVALLIH YQQNQASCGK for Tcells and monocytes, but Swiss-Prot: P78423 RAIILETRQH RLFCADPKEQ notfor neutrophils. The (SEQ ID NO: 12) WVKDAMQHLD RQAAALTRNGmembrane-bound form GTFEKQIGEV KPRTTPAAGG promotes adhesion of thoseMDESVVLEPE ATGESSSLEP leukocytes to endothelial cells. TPSSQEAQRALGTSPELPTG May play a role in regulating VTGSSGTRLP PTPKAQDGGP leukocyteadhesion and VGTELFRVPP VSTAATWQSS migration processes at the APHQPGPSLWAEAKTSEAPS endothelium binds to CX3CR1. TQDPSTQAST ASSPAPEENA PSEGQRVWGQGQSPRPENSL EREEMGPVPA HTDAFQDWGP GSMAHVSVVP VSSEGTPSRE PVASGSWTPKAEEPIHATMD PQRLGVLITP VPDAQAATRR QAVGLLAFLG LLFCLGVAMF TYQSLQGCPRKMAGEMAEGL RYIPRSCGSN SYVLVPV CCL7 (small QPVGINT STTCCYRFIN Chemotacticfactor that attracts inducible cytokine KKIPKQRLES YRRTTSSHCP monocytesand eosinophils, but A7) REAVIFKTKL DKEICADPTQ not neutrophils. AugmentsSwiss-Prot: P80098 KWVQDFMKHL DKKTQTPKL monocyte anti-tumor activity.(SEQ ID NO: 13) Also induces the release of gelatinase B. This proteincan bind heparin. Binds to CCR1, CCR2 and CCR3. Orexin A QPLPDCCRQKTCSCRLYELL Neuropeptide that plays a (Hypocretin-1) HGAGNHAAGI LTLsignificant role in the regulation Swiss-Prot O43612 of food intake andsleep- (SEQ ID NO: 14) wakefulness, possibly by coordinating the complexbehavioral and physiologic responses of these complementary homeostaticfunctions. It plays also a broader role in the homeostatic regulation ofenergy metabolism, autonomic function, hormonal balance and theregulation of body fluids. Orexin-A binds to both OX1R and OX2R with ahigh affinity. Substance P RPK PQQFFGLM Belongs to the tachykinins. (SEQID NO: 15) Tachykinins are active peptides which excite neurons, evokebehavioral responses, are potent vasodilators and secretagogues, andcontract (directly or indirectly) many smooth muscles. QYNADGln-Tyr-Asn-Ala-Asp Acts on voltage-gated sodium (SEQ ID NO: 20)channels.

Glutamate is found in positions 3, 11 and 22 of the amyloid β-peptide.Among them the mutation from glutamic acid (E) to glutamine (Q) inposition 22 (corresponding to amyloid precursor protein APP 693,Swissprot P05067) has been described as the so called Dutch typecerebroarterial amyloidosis mutation.

The β-amyloid peptides with a pyroglutamic acid residue in position 3,11 and/or 22 have been described to be more cytotoxic and hydrophobicthan the amyloid β-peptides 1-40(42/43) (Saido T. C. 2000 MedicalHypotheses 54(3): 427-429).

The multiple N-terminal variations, e.g. Abeta(3-40), Abeta(3-42),Abeta(11-40) and Abeta (11-42) can be generated by the β-secretaseenzyme β-site amyloid precursor protein-cleaving enzyme (BACE) atdifferent sites (Huse J. T. et al. 2002 J. Biol. Chem. 277 (18):16278-16284), and/or by aminopeptidase or dipeptidylaminopeptidaseprocessing from the full length peptides Abeta(1-40) and Abeta(1-42). Inall cases, cyclization of the then N-terminal occurring glutamic acidresidue is catalyzed by QC.

Transepithelial transducing cells, particularly the gastrin (G) cell,co-ordinate gastric acid secretion with the arrival of food in thestomach. Recent work showed that multiple active products are generatedfrom the gastrin precursor, and that there are multiple control pointsin gastrin biosynthesis. Biosynthetic precursors and intermediates(progastrin and Gly-gastrins) are putative growth factors; theirproducts, the amidated gastrins, regulate epithelial cell proliferation,the differentiation of acid-producing parietal cells andhistamine-secreting enterochromaffin-like (ECL) cells, and theexpression of genes associated with histamine synthesis and storage inECL cells, as well as acutely stimulating acid secretion. Gastrin alsostimulates the production of members of the epidermal growth factor(EGF) family, which in turn inhibit parietal cell function but stimulatethe growth of surface epithelial cells. Plasma gastrin concentrationsare elevated in subjects with Helicobacter pylori, who are known to haveincreased risk of duodenal ulcer disease and gastric cancer (Dockray, G.J. 1999 J Physiol 15 315-324).

The peptide hormone gastrin, released from antral G cells, is known tostimulate the synthesis and release of histamine from ECL cells in theoxyntic mucosa via CCK-2 receptors. The mobilized histamine induces acidsecretion by binding to the H(2) receptors located on parietal cells.Recent studies suggest that gastrin, in both its fully amidated and lessprocessed forms (progastrin and glycine-extended gastrin), is also agrowth factor for the gastrointestinal tract. It has been establishedthat the major trophic effect of amidated gastrin is for the oxynticmucosa of stomach, where it causes increased proliferation of gastricstem cells and ECL cells, resulting in increased parietal and ECL cellmass. On the other hand, the major trophic target of the less processedgastrin (e.g. glycine-extended gastrin) appears to be the colonic mucosa(Koh, T. J. and Chen, D. 2000 Regul Pept 9337-44).

Neurotensin (NT) is a neuropeptide implicated in the pathophysiology ofschizophrenia that specifically modulates neurotransmitter systemspreviously demonstrated to be misregulated in this disorder. Clinicalstudies in which cerebrospinal fluid (CSF) NT concentrations have beenmeasured revealed a subset of schizophrenic patients with decreased CSFNT concentrations that are restored by effective antipsychotic drugtreatment. Considerable evidence also exists concordant with theinvolvement of NT systems in the mechanism of action of antipsychoticdrugs. The behavioral and biochemical effects of centrally administeredNT remarkably resemble those of systemically administered antipsychoticdrugs, and antipsychotic drugs increase NT neurotransmission. Thisconcatenation of findings led to the hypothesis that NT functions as anendogenous antipsychotic. Moreover, typical and atypical antipsychoticdrugs differentially alter NT neurotransmission in nigrostriatal andmesolimbic dopamine terminal regions, and these effects are predictiveof side effect liability and efficacy, respectively (Binder, E. B. etal. 2001 Biol Psychiatry 50 856-872).

Fertilization promoting peptide (FPP), a tripeptide related tothyrotrophin releasing hormone (TRH), is found in seminal plasma. Recentevidence obtained in vitro and in vivo showed that FPP plays animportant role in regulating sperm fertility. Specifically, FPPinitially stimulates nonfertilizing (uncapacitated) spermatozoa to“switch on” and become fertile more quickly, but then arrestscapacitation so that spermatozoa do not undergo spontaneous acrosomeloss and therefore do not lose fertilizing potential. These responsesare mimicked, and indeed augmented, by adenosine, known to regulate theadenylyl cyclase (AC)/cAMP signal transduction pathway. Both FPP andadenosine have been shown to stimulate cAMP production in uncapacitatedcells but inhibit it in capacitated cells, with FPP receptors somehowinteracting with adenosine receptors and G proteins to achieveregulation of AC. These events affect the tyrosine phosphorylation stateof various proteins, some being important in the initial “switching on”others possibly being involved in the acrosome reaction itself.Calcitonin and angiotensin II, also found in seminal plasma, havesimilar effects in vitro on uncapacitated spermatozoa and can augmentresponses to FPP. These molecules have similar effects in vivo,affecting fertility by stimulating and then maintaining fertilizingpotential. Either reductions in the availability of FPP, adenosine,calcitonin, and angiotensin II or defects in their receptors contributeto male infertility (Fraser, L. R. and Adeoya-Osiguwa, S. A. 2001 VitamHorm 63, 1-28).

CCL2 (MCP-1), CCL7, CCL8, CCL16, CCL18 and fractalkine play an importantrole in pathophysiological conditions, such as suppression ofproliferation of myeloid progenitor cells, neoplasia, inflammatory hostresponses, cancer, psoriasis, rheumatoid arthritis, atherosclerosis,vasculitis, humoral and cell-mediated immunity responses, leukocyteadhesion and migration processes at the endothelium, inflammatory boweldisease, restenosis, pulmonary fibrosis, pulmonary hypertention, liverfibrosis, liver cirrhosis, nephrosclerosis, ventricular remodeling,heart failure, arteriopathy after organ transplantations and failure ofvein grafts.

A number of studies have underlined in particular the crucial role ofMCP-1 for the development of atherosclerosis (Gu, L., et al., (1998)Mol. Cell 2, 275-281; Gosling, J., et al., (1999) J Clin. Invest 103,773-778); rheumatoid arthritis (Gong, J. H., et al., (1997) J Exp. Med186, 131-137; Ogata, H., et al., (1997) J Pathol. 182, 106-114);pancreatitis (Bhatia, M., et al., (2005) Am. J Physiol Gastrointest.Liver Physiol 288, G1259-G1265); Alzheimer's disease (Yamamoto, M., etal., (2005) Am. J Pathol. 166, 1475-1485); lung fibrosis (Inoshima, I.,et al., (2004) Am. J Physiol Lung Cell Mol. Physiol 286, L1038-L1044);renal fibrosis (Wada, T., et al., (2004) J. Am. Soc. Nephrol. 15,940-948), and graft rejection (Saiura, A., et al., (2004) Arterioscler.Thromb. Vasc. Biol. 24, 1886-1890). Furthermore, MCP-1 might also play arole in gestosis (Katabuchi, H., et al., (2003) Med Electron Microsc.36, 253-262), as a paracrine factor in tumor development (Ohta, M., etal., (2003) Int. J Oncol. 22, 773-778; Li, S., et al., (2005) J. Exp.Med 202, 617-624), neuropathic pain (White, F. A., et al., (2005) Proc.Natl. Acad. Sci. U.S.A) and AIDS (Park, I. W., Wang, J. F., andGroopman, J. E. (2001) Blood 97, 352-358; Coll, B., et al., (2006)Cytokine 34, 51-55).

MCP-1 levels are increased in CSF of AD patients and patients showingmild cognitive impairment (MCI) (Galimberti, D., et al., (2006) Arch.Neurol. 63, 538-543). Furthermore, MCP-1 shows an increased level inserum of patients with MCI and early AD (Clerici, F., et al., (2006)Neurobiol. Aging 27, 1763-1768).

Several cytotoxic T lymphocyte peptide-based vaccines against hepatitisB, human immunodeficiency virus and melanoma were recently studied inclinical trials. One interesting melanoma vaccine candidate alone or incombination with other tumor antigens, is the decapeptide ELA. Thispeptide is a Melan-A/MART-1 antigen immunodominant peptide analog, withan N-terminal glutamic acid. It has been reported that the amino groupand gamma-carboxylic group of glutamic acids, as well as the amino groupand gamma-carboxamide group of glutamines, condense easily to formpyroglutamic derivatives. To overcome this stability problem, severalpeptides of pharmaceutical interest have been developed with apyroglutamic acid instead of N-terminal glutamine or glutamic acid,without loss of pharmacological properties. Unfortunately compared withELA, the pyroglutamic acid derivative (PyrELA) and also the N-terminalacetyl-capped derivative (AcELA) failed to elicit cytotoxic T lymphocyte(CTL) activity. Despite the apparent minor modifications introduced inPyrELA and AcELA, these two derivatives probably have lower affinitythan ELA for the specific class I major histocompatibility complex.Consequently, in order to conserve full activity of ELA, the formationof PyrELA must be avoided (Beck A. et al. 2001, J Pept Res57(6):528-38.).

Orexin A is a neuropeptide that plays a significant role in theregulation of food intake and sleep-wakefulness, possibly bycoordinating the complex behavioral and physiologic responses of thesecomplementary homeostatic functions. It plays also a role in thehomeostatic regulation of energy metabolism, autonomic function,hormonal balance and the regulation of body fluids.

Recently, increased levels of the pentapeptide QYNAD were identified inthe cerebrospinal fluid (CSF) of patients suffering from multiplesclerosis or Guillain-Barré syndrome compared to healthy individuals(Brinkmeier H. et al. 2000, Nature Medicine 6, 808-811). There is a bigcontroversy in the literature about the mechanism of action of thepentapeptide Gln-Tyr-Asn-Ala-Asp (QYNAD), especially its efficacy tointeract with and block sodium channels resulting in the promotion ofaxonal dysfunction, which are involved in inflammatory autoimmunediseases of the central nervous system. But recently, it could bedemonstrated that not QYNAD, but its cyclized, pyroglutamated form,pEYNAD, is the active form, which blocks sodium channels resulting inthe promotion of axonal dysfunction. Sodium channels are expressed athigh density in myelinated axons and play an obligatory role inconducting action potentials along axons within the mammalian brain andspinal cord. Therefore, it is speculated that they are involved inseveral aspects of the pathophysiology of inflammatory autoimmunediseases, especially multiple sclerosis, the Guillain-Barré syndrome andchronic inflammatory demyelinizing polyradiculoneuropathy.

Furthermore, QYNAD is a substrate of the enzyme glutaminyl cyclase (QC,EC 2.3.2.5), which is also present in the brain of mammals, especiallyin human brain. Glutaminyl cyclase catalyzes effectively the formationof pEYNAD from its precursor QYNAD.

Accordingly, the present invention provides the use of the compounds offormula (I) for the preparation of a medicament for the prevention oralleviation or treatment of a disease selected from the group consistingof mild cognitive impairment, Alzheimer's disease, Familial BritishDementia, Familial Danish Dementia, neurodegeneration in Down Syndrome,Huntington's disease, Kennedy's disease, ulcer disease, duodenal cancerwith or w/o Helicobacter pylori infections, colorectal cancer,Zolliger-Ellison syndrome, gastric cancer with or without Helicobacterpylori infections, pathogenic psychotic conditions, schizophrenia,infertility, neoplasia, inflammatory host responses, cancer, malignmetastasis, melanoma, psoriasis, rheumatoid arthritis, atherosclerosis,pancreatitis, restenosis, impaired humoral and cell-mediated immuneresponses, leukocyte adhesion and migration processes in theendothelium, impaired food intake, impaired sleep-wakefulness, impairedhomeostatic regulation of energy metabolism, impaired autonomicfunction, impaired hormonal balance or impaired regulation of bodyfluids, multiple sclerosis, the Guillain-Barré syndrome and chronicinflammatory demyelinizing polyradiculoneuropathy.

Furthermore, by administration of a compound according to the presentinvention to a mammal it can be possible to stimulate the proliferationof myeloid progenitor cells.

In addition, the administration of a QC inhibitor according to thepresent invention can lead to suppression of male fertility.

In a preferred embodiment, the present invention provides the use ofinhibitors of QC (EC) activity in combination with other agents,especially for the treatment of neuronal diseases, artherosclerosis andmultiple sclerosis.

The present invention also provides a method of treatment of theaforementioned diseases comprising the administration of atherapeutically active amount of at least one compound of formula (I) toa mammal, preferably a human.

Most preferably, said method and corresponding uses are for thetreatment of a disease selected from the group consisting of mildcognitive impairment, Alzheimer's disease, Familial British Dementia,Familial Danish Dementia, neurodegeneration in Down Syndrome,Parkinson's disease and Chorea Huntington, comprising the administrationof a therapeutically active amount of at least one compound of formula(I) to a mammal, preferably a human.

Even preferably, the present invention provides a method of treatmentand corresponding uses for the treatment of rheumatoid arthritis,atherosclerosis, pancreatitis and restenosis.

Inhibiting Conversion to Pyroglutamic Acid Residues

The present invention also provides methods of inhibiting the conversionof N-terminal glutamic acid or glutamine residues to pyroglutamic acidresidues of at least one substrate of glutaminyl cyclase in mammaliansubjects. Compounds and/or compositions described herein can beadministered to a mammalian subject. Substrates of glutaminyl cyclasecan be as described herein. The mammalian subject can be in need of suchadministration, such need including diagnosis of, or at risk for, adisease or condition described above. For example, a therapeuticallyeffective amount of a pharmaceutical composition comprising an inhibitorof glutaminyl cyclase can be administered to a mammalian subject in needthereof so as to inhibit the conversion of N-terminal glutamic acid orglutamine residues to pyroglutamic acid residues of at least onesubstrate of glutaminyl cyclase in the subject. In some embodiments, themethod can further include observing a therapeutic effect of theadministration of the inhibitor.

Pharmaceutical Combinations

In a preferred embodiment, the present invention provides a composition,preferably a pharmaceutical composition, comprising at least one QCinhibitor optionally in combination with at least one other agentselected from the group consisting of nootropic agents,neuroprotectants, antiparkinsonian drugs, amyloid protein depositioninhibitors, beta amyloid synthesis inhibitors, antidepressants,anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.

Most preferably, said QC inhibitor is a compound of formula (I) of thepresent invention.

More specifically, the aforementioned other agent is selected from thegroup consisting of beta-amyloid antibodies, cysteine proteaseinhibitors, PEP-inhibitors, LiCl, acetylcholinesterase (AChE)inhibitors, PIMT enhancers, inhibitors of beta secretases, inhibitors ofgamma secretases, inhibitors of aminopeptidases, preferably inhibitorsof dipeptidyl peptidases, most preferably DP IV inhibitors; inhibitorsof neutral endopeptidase, inhibitors of Phosphodiesterase-4 (PDE-4),TNFalpha inhibitors, muscarinic M1 receptor antagonists, NMDA receptorantagonists, sigma-1 receptor inhibitors, histamine H3 antagonists,immunomodulatory agents, immunosuppressive agents, MCP-1 antagonists oran agent selected from the group consisting of antegren (natalizumab),Neurelan (fampridine-SR), campath (alemtuzumab), IR 208, NBI 5788/MSP771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD271, adapalene), BAY 361677 (interleukin-4),matrix-metalloproteinase-inhibitors (e.g. BB 76163), interferon-tau(trophoblastin) and SAIK-MS.

Furthermore, the other agent may be, for example, an anti-anxiety drugor antidepressant selected from the group consisting of

-   -   (a) Benzodiazepines, e.g. alprazolam, chlordiazepoxide,        clobazam, clonazepam, clorazepate, diazepam, fludiazepam,        loflazepate, lorazepam, methaqualone, oxazepam, prazepam,        tranxene,    -   (b) Selective serotonin re-uptake inhibitors (SSRI's), e.g.        citalopram, fluoxetine, fluvoxamine, escitalopram, sertraline,        paroxetine,    -   (c) Tricyclic antidepressants, e.g. amitryptiline, clomipramine,        desipramine, doxepin, imipramine    -   (d) Monoamine oxidase (MAO) inhibitors,    -   (e) Azapirones, e.g. buspirone, tandopsirone,    -   (f) Serotonin-norepinephrine reuptake inhibitors (SNRI's), e.g.        venlafaxine, duloxetine,    -   (g) Mirtazapine,    -   (h) Norepinephrine reuptake inhibitors (NRI's), e.g. reboxetine,    -   (i) Bupropione,    -   (j) Nefazodone,    -   (k) beta-blockers,    -   (l) NPY-receptor ligands: NPY agonists or antagonists.

In a further embodiment, the other agent may be, for example, ananti-multiple sclerosis drug selected from the group consisting of

-   -   a) dihydroorotate dehydrogenase inhibitors, e.g. SC-12267,        teriflunomide, MNA-715, HMR-1279 (syn. to HMR-1715, MNA-279),    -   b) autoimmune suppressant, e.g. laquinimod,    -   c) paclitaxel,    -   d) antibodies, e.g. AGT-1, anti-granulocyte-macrophage        colony-stimulating factor (GM-CSF) monoclonal antibody, Nogo        receptor modulators, ABT-874, alemtuzumab (CAMPATH), anti-OX40        antibody, CNTO-1275, DN-1921, natalizumab (syn. to AN-100226,        Antegren, VLA-4 Mab), daclizumab (syn. to Zenepax, Ro-34-7375,        SMART anti-Tac), J-695, priliximab (syn. to Centara, CEN-000029,        cM-T412), MRA, Dantes, anti-IL-12-antibody,    -   e) peptide nucleic acid (PNA) preparations, e.g. reticulose,    -   f) interferon alpha, e.g. Alfaferone, human alpha interferon        (syn. to Omniferon, Alpha Leukoferon),    -   g) interferon beta, e.g. Frone, interferon beta-1a like Avonex,        Betron (Rebif), interferon beta analogs, interferon        beta-transferrin fusion protein, recombinant interferon beta-1b        like Betaseron,    -   h) interferon tau,    -   i) peptides, e.g. AT-008, AnergiX.MS, Immunokine        (alpha-Immunokine-NNSO3), cyclic peptides like ZD-7349,    -   j) therapeutic enzymes, e.g. soluble CD8 (sCD8),    -   k) multiple sclerosis-specific autoantigen-encoding plasmid and        cytokine-encoding plasmid, e.g. BHT-3009;    -   l) inhibitor of TNF-alpha, e.g. BLX-1002, thalidomide, SH-636,    -   m) TNF antagonists, e.g. solimastat, lenercept (syn. to        RO-45-2081, Tenefuse), onercept (sTNFR1), CC-1069,    -   n) TNF alpha, e.g. etanercept (syn. to Enbrel, TNR-001)    -   o) CD28 antagonists, e.g. abatacept,    -   p) Lck tyrosine kinase inhibitors,    -   q) cathepsin K inhibitors,    -   r) analogs of the neuron-targeting membrane transporter protein        taurine and the plant-derived calpain inhibitor leupeptin, e.g.        Neurodur,    -   s) chemokine receptor-1 (CCR1) antagonist, e.g. BX-471,    -   t) CCR2 antagonists,    -   u) AMPA receptor antagonists, e.g. ER-167288-01 and ER-099487,        E-2007, talampanel,    -   v) potassium channel blockers, e.g. fampridine,    -   w) tosyl-proline-phenylalanine small-molecule antagonists of the        VLA-4/VCAM interaction, e.g. TBC-3342,    -   x) cell adhesion molecule inhibitors, e.g. TBC-772,    -   y) antisense oligonucleotides, e.g. EN-101,    -   z) antagonists of free immunoglobulin light chain (IgLC) binding        to mast cell receptors, e.g. F-991,    -   aa) apoptosis inducing antigens, e.g. Apogen MS,    -   bb) alpha-2 adrenoceptor agonist, e.g. tizanidine (syn. to        Zanaflex, Ternelin, Sirdalvo, Sirdalud, Mionidine),    -   cc) copolymer of L-tyrosine, L-lysine, L-glutamic acid and        L-alanine, e.g. glatiramer acetate (syn. to Copaxone, COP-1,        copolymer-),    -   dd) topoisomerase II modulators, e.g. mitoxantrone        hydrochloride,    -   ee) adenosine deaminase inhibitor, e.g. cladribine (syn. to        Leustatin, Mylinax, RWJ-26251),    -   ff) interleukin-10, e.g. ilodecakin (syn. to Tenovil, Sch-52000,        CSIF),    -   gg) interleukin-12 antagonists, e.g. lisofylline (syn. to        CT-1501R, LSF, lysofylline),    -   hh) Ethanaminum, e.g. SRI-62-834 (syn. to CRC-8605, NSC-614383),    -   ii) immunomodulators, e.g. SAIK-MS, PNU-156804,        alpha-fetoprotein peptide (AFP), IPDS,    -   jj) retinoid receptor agonists, e.g. adapalene (syn. to        Differin, CD-271),    -   kk) TGF-beta, e.g. GDF-1 (growth and differentiation factor 1),    -   ll) TGF-beta-2, e.g. BetaKine,    -   mm) MMP inhibitors, e.g. glycomed,    -   nn) phosphodiesterase 4 (PDE4) inhibitors, e.g. RPR-122818,    -   oo) purine nucleoside phosphorylase inhibitors, e.g.        9-(3-pyridylmethyl)-9-deazaguanine, peldesine (syn. to BCX-34,        TO-200),    -   pp) alpha-4/beta-1 integrin antagonists, e.g. ISIS-104278,    -   qq) antisense alpha4 integrin (CD49d), e.g. ISIS-17044,        ISIS-27104,    -   rr) cytokine-inducing agents, e.g. nucleosides, ICN-17261,    -   ss) cytokine inhibitors,    -   tt) heat shock protein vaccines, e.g. HSPPC-96,    -   uu) neuregulin growth factors, e.g. GGF-2 (syn. to neuregulin,        glial growth factor 2),    -   vv) cathepsin S-inhibitors,    -   ww) bropirimine analogs, e.g. PNU-56169, PNU-63693,    -   xx) Monocyte chemoattractant protein-1 inhibitors, e.g.        benzimidazoles like MCP-1 inhibitors, LKS-1456, PD-064036,        PD-064126, PD-084486, PD-172084, PD-172386.

Further, the present invention provides pharmaceutical compositions e.g.for parenteral, enteral or oral administration, comprising at least oneQC inhibitor, optionally in combination with at least one of the otheraforementioned agents.

These combinations provide a particularly beneficial effect. Suchcombinations are therefore shown to be effective and useful for thetreatment of the aforementioned diseases. Accordingly, the inventionprovides a method for the treatment of these conditions.

The method comprises either co-administration of at least one QCinhibitor and at least one of the other agents or the sequentialadministration thereof.

Co-administration includes administration of a formulation, whichcomprises at least one QC inhibitor and at least one of the other agentsor the essentially simultaneous administration of separate formulationsof each agent.

Beta-amyloid antibodies and compositions containing the same aredescribed, e.g. in WO 2006/137354, WO 2006/118959, WO 2006/103116, WO2006/095041, WO 2006/081171, WO 2006/066233, WO 2006/066171, WO2006/066089, WO 2006/066049, WO 2006/055178, WO 2006/046644, WO2006/039470, WO 2006/036291, WO 2006/026408, WO 2006/016644, WO2006/014638, WO 2006/014478, WO 2006/008661, WO 2005/123775, WO2005/120571, WO 2005/105998, WO 2005/081872, WO 2005/080435, WO2005/028511, WO 2005/025616, WO 2005/025516, WO 2005/023858, WO2005/018424, WO 2005/011599, WO 2005/000193, WO 2004/108895, WO2004/098631, WO 2004/080419, WO 2004/071408, WO 2004/069182, WO2004/067561, WO 2004/044204, WO 2004/032868, WO 2004/031400, WO2004/029630, WO 2004/029629, WO 2004/024770, WO 2004/024090, WO2003/104437, WO 2003/089460, WO 2003/086310, WO 2003/077858, WO2003/074081, WO 2003/070760, WO 2003/063760, WO 2003/055514, WO2003/051374, WO 2003/048204, WO 2003/045128, WO 2003/040183, WO2003/039467, WO 2003/016466, WO 2003/015691, WO 2003/014162, WO2003/012141, WO 2002/088307, WO 2002/088306, WO 2002/074240, WO2002/046237, WO 2002/046222, WO 2002/041842, WO 2001/062801, WO2001/012598, WO 2000/077178, WO 2000/072880, WO 2000/063250, WO1999/060024, WO 1999/027944, WO 1998/044955, WO 1996/025435, WO1994/017197, WO 1990/014840, WO 1990/012871, WO 1990/012870, WO1989/006242.

The beta-amyloid antibodies may be selected from, for example,polyclonal, monoclonal, chimenic or humanized antibodies. Furthermore,said antibodies may be useful to develop active and passive immunetherapies, i.e. vaccines and monoclonal antibodies. Suitable examples ofbeta-amyloid antibodies are ACU-5A5, huC091 (Acumen/Merck); PF-4360365,RI-1014, RI-1219, RI-409, RN-1219 (Rinat Neuroscience Corp (PfizerInc)); the nanobody therapeutics of Ablynx/Boehringer Ingelheim;beta-amyloid-specific humanized monoclonal antibodies of IntellectNeurosciences/IBL; m266, m266.2 (Eli Lilly & Co.); AAB-02 (Elan);bapineuzumab (Elan); BAN-2401 (Bioarctic Neuroscience AB); ABP-102(Abiogen Pharma SpA); BA-27, BC-05 (Takeda); R-1450 (Roche); ESBA-212(ESBATech AG); AZD-3102 (AstraZeneca) and beta-amyloid antibodies ofMindset BioPharmaceuticals Inc. Especially preferred are antibodies,which recognize the N-terminus of the Aβ peptide. A suitable antibody,which recognizes the Aβ-N-Terminus is, for example Acl-24 (AC ImmuneSA). A monoclonal antibody against beta-amyloid peptide is disclosed inWO 2007/068412. Respective chimeric and humanized antibodies aredisclosed in WO 2008/011348. A method for producing a vaccinecomposition for treating an amyloid-associated disease is disclosed inWO 2007/068411.

Suitable cysteine protease inhibitors are inhibitors of cathepsin B.Inhibitors of cathepsin B and compositions containing such inhibitorsare described, e.g. in WO 2006/060473, WO 2006/042103, WO 2006/039807,WO 2006/021413, WO 2006/021409, WO 2005/097103, WO 2005/007199,WO2004/084830, WO 2004/078908, WO 2004/026851, WO 2002/094881, WO2002/027418, WO 2002/021509, WO 1998/046559, WO 1996/021655.

Examples of suitable PIMT enhancers are 10-aminoaliphatyl-dibenz[b,f]oxepines described in WO 98/15647 and WO 03/057204, respectively.Further useful according to the present invention are modulators of PIMTactivity described in WO 2004/039773.

Inhibitors of beta secretase and compositions containing such inhibitorsare described, e.g. in WO03/059346, WO2006/099352, WO2006/078576,WO2006/060109, WO2006/057983, WO2006/057945, WO2006/055434,WO2006/044497, WO2006/034296, WO2006/034277, WO2006/029850,WO2006/026204, WO2006/014944, WO2006/014762, WO2006/002004, U.S. Pat.No. 7,109,217, WO2005/113484, WO2005/103043, WO2005/103020,WO2005/065195, WO2005/051914, WO2005/044830, WO2005/032471,WO2005/018545, WO2005/004803, WO2005/004802, WO2004/062625,WO2004/043916, WO2004/013098, WO03/099202, WO03/043987, WO03/039454,U.S. Pat. No. 6,562,783, WO02/098849 and WO02/096897.

Suitable examples of beta secretase inhibitors for the purpose of thepresent invention are WY-25105 (Wyeth); Posiphen, (+)-phenserine(TorreyPines/NIH); LSN-2434074, LY-2070275, LY-2070273, LY-2070102 (EliLilly & Co.); PNU-159775A, PNU-178025A, PNU-17820A, PNU-33312,PNU-38773, PNU-90530 (Elan/Pfizer); KMI-370, KMI-358, kmi-008 (KyotoUniversity); OM-99-2, OM-003 (Athenagen Inc.); AZ-12304146(AstraZeneca/Astex); GW-840736X (GlaxoSmithKline plc.), DNP-004089 (DeNovo Pharmaceuticals Ltd.) and CT-21166 (CoMentis Inc.).

Inhibitors of gamma secretase and compositions containing suchinhibitors are described, e.g. in WO2005/008250, WO2006/004880, U.S.Pat. No. 7,122,675, U.S. Pat. No. 7,030,239, U.S. Pat. No. 6,992,081,U.S. Pat. No. 6,982,264, WO2005/097768, WO2005/028440, WO2004/101562,U.S. Pat. No. 6,756,511, U.S. Pat. No. 6,683,091, WO03/066592,WO03/014075, WO03/013527, WO02/36555, WO01/53255, U.S. Pat. No.7,109,217, U.S. Pat. No. 7,101,895, U.S. Pat. No. 7,049,296, U.S. Pat.No. 7,034,182, U.S. Pat. No. 6,984,626, WO2005/040126, WO2005/030731,WO2005/014553, U.S. Pat. No. 6,890,956, EP 1334085, EP 1263774,WO2004/101538, WO2004/00958, WO2004/089911, WO2004/073630,WO2004/069826, WO2004/039370, WO2004/031139, WO2004/031137, U.S. Pat.No. 6,713,276, U.S. Pat. No. 6,686,449, WO03/091278, U.S. Pat. No.6,649,196, U.S. Pat. No. 6,448,229, WO01/77144 and WO01/66564.

Suitable gamma secretase inhibitors for the purpose of the presentinvention are GSI-953, WAY-GSI-A, WAY-GSI-B (Wyeth); MK-0752, MRK-560,L-852505, L-685-458, L-852631, L-852646 (Merck & Co. Inc.); LY-450139,LY-411575, AN-37124 (Eli Lilly & Co.); BMS-299897, BMS-433796(Bristol-Myers Squibb Co.); E-2012 (Eisai Co. Ltd.); EHT-0206, EHT-206(ExonHit Therapeutics SA); and NGX-555 (TorreyPines Therapeutics Inc.).

DP IV-inhibitors and compositions containing such inhibitors aredescribed, e.g. in U.S. Pat. No. 6,011,155; U.S. Pat. No. 6,107,317;U.S. Pat. No. 6,110,949; U.S. Pat. No. 6,124,305; U.S. Pat. No.6,172,081; WO99/61431, WO99/67278, WO99/67279, DE19834591, WO97/40832,WO95/15309, WO98/19998, WO0/07617, WO99/38501, WO99/46272, WO99/38501,WO01/68603, WO01/40180, WO01/81337, WO1/81304, WO01/55105, WO02/02560,WO01/34594, WO02/38541, WO02/083128, WO03/072556, WO03/002593,WO03/000250, WO03/000180, WO03/000181, EP1258476, WO03/002553,WO03/002531, WO03/002530, WO03/004496, WO03/004498, WO03/024942,WO03/024965, WO03/033524, WO03/035057, WO03/035067, WO03/037327,WO03/040174, WO03/045977, WO03/055881, WO03/057144, WO03/057666,WO03/068748, WO03/068757, WO03/082817, WO03/101449, WO03/101958,WO03/104229, WO03/74500, WO2004/007446, WO2004/007468, WO2004/018467,WO2004/018468, WO2004/018469, WO2004/026822, WO2004/032836,WO2004/033455, WO2004/037169, WO2004/041795, WO2004/043940,WO2004/048352, WO2004/050022, WO2004/052850, WO2004/058266,WO2004/064778, WO2004/069162, WO2004/071454, WO2004/076433,WO2004/076434, WO2004/087053, WO2004/089362, WO2004/099185,WO2004/103276, WO2004/103993, WO2004/108730, WO2004/110436,WO2004/111041, WO2004/112701, WO2005/000846, WO2005/000848,WO2005/011581, WO2005/016911, WO2005/023762, WO2005/025554,WO2005/026148, WO2005/030751, WO2005/033106, WO2005/037828,WO2005/040095, WO2005/044195, WO2005/047297, WO2005/051950,WO2005/056003, WO2005/056013, WO2005/058849, WO2005/075426,WO2005/082348, WO2005/085246, WO2005/087235, WO2005/095339,WO2005/095343, WO2005/095381, WO2005/108382, WO2005/113510,WO2005/116014, WO2005/116029, WO2005/118555, WO2005/120494,WO2005/121089, WO2005/121131, WO2005/123685, WO2006/995613;WO2006/009886; WO2006/013104; WO2006/017292; WO2006/019965;WO2006/020017; WO2006/023750; WO2006/039325; WO2006/041976;WO2006/047248; WO2006/058064; WO2006/058628; WO2006/066747;WO2006/066770 and WO2006/068978.

Suitable DP IV-inhibitors for the purpose of the present invention arefor example Sitagliptin, des-fluoro-sitagliptin (Merck & Co. Inc.);vildagliptin, DPP-728, SDZ-272-070 (Novartis); ABT-279, ABT-341 (AbbottLaboratories); denagliptin, TA-6666 (GlaxoSmithKline plc.); SYR-322(Takeda San Diego Inc.); talabostat (Point Therapeutics Inc.);Ro-0730699, R-1499, R-1438 (Roche Holding AG); FE-999011 (FerringPharmaceuticals); TS-021 (Taisho Pharmaceutical Co. Ltd.); GRC-8200(Glenmark Pharmaceuticals Ltd.); ALS-2-0426 (Alantos PharmaceuticalsHolding Inc.); ARI-2243 (Arisaph Pharmaceuticals Inc.); SSR-162369(Sanofi-Synthelabo); MP-513 (Mitsubishi Pharma Corp.); DP-893,CP-867534-01 (Pfizer Inc.); TSL-225, TMC-2A (Tanabe Seiyaku Co. Ltd.);PHX-1149 (Phenomenix Corp.); saxagliptin (Bristol-Myers Squibb Co.);PSN-9301 ((OSI) Prosidion), S-40755 (Servier); KRP-104 (ActivXBiosciences Inc.); sulphostin (Zaidan Hojin); KR-62436 (Korea ResearchInstitute of Chemical Technology); P32/98 (Probiodrug AG); BI-A, BI-B(Boehringer Ingelheim Corp.); SK-0403 (Sanwa Kagaku Kenkyusho Co. Ltd.);and NNC-72-2138 (Novo Nordisk A/S).

Other preferred DP IV-inhibitors are

(i) dipeptide-like compounds, disclosed in WO 99/61431, e.g. N-valylprolyl, O-benzoyl hydroxylamine, alanyl pyrrolidine, isoleucylthiazolidine like L-allo-isoleucyl thiazolidine, L-threo-isoleucylpyrrolidine and salts thereof, especially the fumaric salts, andL-allo-isoleucyl pyrrolidine and salts thereof;(ii) peptide structures, disclosed in WO 03/002593, e.g. tripeptides;(iii) peptidylketones, disclosed in WO 03/033524;(vi) substituted aminoketones, disclosed in WO 03/040174;(v) topically active DP IV-inhibitors, disclosed in WO 01/14318;(vi) prodrugs of DP IV-inhibitors, disclosed in WO 99/67278 and WO99/67279; and(v) glutaminyl based DP IV-inhibitors, disclosed in WO 03/072556 and WO2004/099134.

Suitable beta amyloid synthesis inhibitors for the purpose of thepresent invention are for example Bisnorcymserine (Axonyx Inc.);(R)-flurbiprofen (MCP-7869; Flurizan) (Myriad Genetics);nitroflurbiprofen (NicOx); BGC-20-0406 (Sankyo Co. Ltd.) and BGC-20-0466(BTG plc.).

Suitable amyloid protein deposition inhibitors for the purpose of thepresent invention are for example SP-233 (Samaritan Pharmaceuticals);AZD-103 (Ellipsis Neurotherapeutics Inc.); AAB-001 (Bapineuzumab),AAB-002, ACC-001 (Elan Corp plc.); Colostrinin (ReGen Therapeuticsplc.); Tramiprosate (Neurochem); AdPEDI-(amyloid-beta1-6)₁₋₁) (VaxinInc.); MPI-127585, MPI-423948 (Mayo Foundation); SP-08 (GeorgetownUniversity); ACU-5A5 (Acumen/Merck); Transthyretin (State University ofNew York); PTI-777, DP-74, DP 68, Exebryl (ProteoTech Inc.); m266 (EliLilly & Co.); EGb-761 (Dr. Willmar Schwabe GmbH); SPI-014 (SatoriPharmaceuticals Inc.); ALS-633, ALS-499 (Advanced Life Sciences Inc.);AGT-160 (ArmaGen Technologies Inc.); TAK-070 (Takeda Pharmaceutical Co.Ltd.); CHF-5022, CHF-5074, CHF-5096 and CHF-5105 (Chiesi FarmaceuticiSpA.).

Suitable PDE-4 inhibitors for the purpose of the present invention arefor example Doxofylline (Instituto Biologico Chemioterapica ABC SpA.);idudilast eye drops, tipelukast, ibudilast (Kyorin Pharmaceutical Co.Ltd.); theophylline (Elan Corp.); cilomilast (GlaxoSmithKline plc.);Atopik (Barrier Therapeutics Inc.); tofimilast, CI-1044, PD-189659,CP-220629, PDE 4d inhibitor BHN (Pfizer Inc.); arofylline, LAS-37779(Almirall Prodesfarma SA.); roflumilast, hydroxypumafentrine (AltanaAG), tetomilast (Otska Pharmaceutical Co. Ltd.); tipelukast, ibudilast(Kyorin Pharmaceutical), CC-10004 (Celgene Corp.); HT-0712, IPL-4088(Inflazyme Pharmaceuticals Ltd.); MEM-1414, MEM-1917 (MemoryPharmaceuticals Corp.); oglemilast, GRC-4039 (Glenmark PharmaceuticalsLtd.); AWD-12-281, ELB-353, ELB-526 (Elbion AG); EHT-0202 (ExonHitTherapeutics SA.); ND-1251 (Neuro3d SA.); 4AZA-PDE4 (4 AZA BioscienceNV.); AVE-8112 (Sanofi-Aventis); CR-3465 (Rottapharm SpA.); GP-0203,NCS-613 (Centre National de la Recherche Scientifique); KF-19514 (KyowaHakko Kogyo Co. Ltd.); ONO-6126 (Ono Pharmaceutical Co. Ltd.); OS-0217(Dainippon Pharmaceutical Co. Ltd.); IBFB-130011, IBFB-150007,IBFB-130020, IBFB-140301 (IBFB Pharma GmbH); IC-485 (ICOS Corp.);RBx-14016 and RBx-11082 (Ranbaxy Laboratories Ltd.). A preferredPDE-4-inhibitor is Rolipram.

MAO inhibitors and compositions containing such inhibitors aredescribed, e.g. in WO2006/091988, WO2005/007614, WO2004/089351,WO01/26656, WO01/12176, WO99/57120, WO99/57119, WO99/13878, WO98/40102,WO98/01157, WO96/20946, WO94/07890 and WO92/21333.

Suitable MAO-inhibitors for the purpose of the present invention are forexample Linezolid (Pharmacia Corp.); RWJ-416-457 (RW JohnsonPharmaceutical Research Institute); budipine (Altana AG); GPX-325(BioResearch Ireland); isocarboxazid; phenelzine; tranylcypromine;indantadol (Chiesi Farmaceutici SpA.); moclobemide (Roche Holding AG);SL-25.1131 (Sanofi-Synthelabo); CX-1370 (Burroughs Wellcome Co.); CX-157(Krenitsky Pharmaceuticals Inc.); desoxypeganine (HFArzneimittelforschung GmbH & Co. KG); bifemelane (Mitsubishi-TokyoPharmaceuticals Inc.); RS-1636 (Sankyo Co. Ltd.); esuprone (BASF AG);rasagiline (Teva Pharmaceutical Industries Ltd.); ladostigil (HebrewUniversity of Jerusalem); safinamide (Pfizer) and NW-1048 (NewronPharmaceuticals SpA.).

Suitable histamine H3 antagonists for the purpose of the presentinvention are, e.g. ABT-239, ABT-834 (Abbott Laboratories); 3874-H1(Aventis Pharma); UCL-2173 (Berlin Free University), UCL-1470(BioProjet, Societe Civile de Recherche); DWP-302 (DaewoongPharmaceutical Co Ltd); GSK-189254A, GSK-207040A (GlaxoSmithKline Inc.);cipralisant, GT-2203 (Gliatech Inc.); Ciproxifan (INSERM),1S,2S-2-(2-Aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane (HokkaidoUniversity); JNJ-17216498, JNJ-5207852 (Johnson & Johnson);NNC-0038-0000-1049 (Novo Nordisk A/S); and Sch-79687 (Schering-Plough).

PEP inhibitors and compositions containing such inhibitors aredescribed, e.g. in JP 01042465, JP 03031298, JP 04208299, WO 00/71144,U.S. Pat. No. 5,847,155; JP 09040693, JP 10077300, JP 05331072, JP05015314, WO 95/15310, WO 93/00361, EP 0556482, JP 06234693, JP01068396, EP 0709373, U.S. Pat. No. 5,965,556, U.S. Pat. No. 5,756,763,U.S. Pat. No. 6,121,311, JP 63264454, JP 64000069, JP 63162672, EP0268190, EP 0277588, EP 0275482, U.S. Pat. No. 4,977,180, U.S. Pat. No.5,091,406, U.S. Pat. No. 4,983,624, U.S. Pat. No. 5,112,847, U.S. Pat.No. 5,100,904, U.S. Pat. No. 5,254,550, U.S. Pat. No. 5,262,431, U.S.Pat. No. 5,340,832, U.S. Pat. No. 4,956,380, EP 0303434, JP 03056486, JP01143897, JP 1226880, EP 0280956, U.S. Pat. No. 4,857,537, EP 0461677,EP 0345428, JP 02275858, U.S. Pat. No. 5,506,256, JP 06192298, EP0618193, JP 03255080, EP 0468469, U.S. Pat. No. 5,118,811, JP 05025125,WO 9313065, JP 05201970, WO 9412474, EP 0670309, EP 0451547, JP06339390, U.S. Pat. No. 5,073,549, U.S. Pat. No. 4,999,349, EP 0268281,U.S. Pat. No. 4,743,616, EP 0232849, EP 0224272, JP 62114978, JP62114957, U.S. Pat. No. 4,757,083, U.S. Pat. No. 4,810,721, U.S. Pat.No. 5,198,458, U.S. Pat. No. 4,826,870, EP 0201742, EP 0201741, U.S.Pat. No. 4,873,342, EP 0172458, JP 61037764, EP 0201743, U.S. Pat. No.4,772,587, EP 0372484, U.S. Pat. No. 5,028,604, WO 91/18877, JP04009367, JP 04235162, U.S. Pat. No. 5,407,950, WO 95/01352, JP01250370, JP 02207070, U.S. Pat. No. 5,221,752, EP 0468339, JP 04211648,WO 99/46272, WO 2006/058720 and PCT/EP2006/061428.

Suitable prolyl endopeptidase inhibitors for the purpose of the presentinvention are, e.g. Fmoc-Ala-Pyrr-CN, Z-Phe-Pro-Benzothiazole(Probiodrug), Z-321 (Zeria Pharmaceutical Co Ltd.); ONO-1603 (OnoPharmaceutical Co Ltd); JTP-4819 (Japan Tobacco Inc.) and S-17092(Servier).

Other suitable compounds that can be used according to the presentinvention in combination with QC-inhibitors are NPY, an NPY mimetic oran NPY agonist or antagonist or a ligand of the NPY receptors.

Preferred according to the present invention are antagonists of the NPYreceptors.

Suitable ligands or antagonists of the NPY receptors are3a,4,5,9b-tetrahydro-1 h-benz[e]indol-2-yl amine-derived compounds asdisclosed in WO 00/68197.

NPY receptor antagonists which may be mentioned include those disclosedin European patent applications EP 0 614 911, EP 0 747 357, EP 0 747 356and EP 0 747 378; international patent applications WO 94/17035, WO97/19911, WO 97/19913, WO 96/12489, WO 97/19914, WO 96/22305, WO96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821, WO97/20822, WO 97/20823, WO 97/19682, WO 97/25041, WO 97/34843, WO97/46250, WO 98/03492, WO 98/03493, WO 98/03494 and WO 98/07420; WO00/30674, U.S. Pat. Nos. 5,552,411, 5,663,192 and 5,567,714; 6,114,336,Japanese patent application JP 09157253; international patentapplications WO 94/00486, WO 93/12139, WO 95/00161 and WO 99/15498; U.S.Pat. No. 5,328,899; German patent application DE 393 97 97; Europeanpatent applications EP 355 794 and EP 355 793; and Japanese patentapplications JP 06116284 and JP 07267988. Preferred NPY antagonistsinclude those compounds that are specifically disclosed in these patentdocuments. More preferred compounds include amino acid andnon-peptide-based NPY antagonists. Amino acid and non-peptide-based NPYantagonists which may be mentioned include those disclosed in Europeanpatent applications EP 0 614 911, EP 0 747 357, EP 0 747 356 and EP 0747 378; international patent applications WO 94/17035, WO 97/19911, WO97/19913, WO 96/12489, WO 97/19914, WO 96/22305, WO 96/40660, WO96/12490, WO 97/09308, WO 97/20820, WO 97/20821, WO 97/20822, WO97/20823, WO 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO98/03492, WO 98/03493, WO 98/03494, WO 98/07420 and WO 99/15498; U.S.Pat. Nos. 5,552,411, 5,663,192 and 5,567,714; and Japanese patentapplication JP 09157253. Preferred amino acid and non-peptide-based NPYantagonists include those compounds that are specifically disclosed inthese patent documents.

Particularly preferred compounds include amino acid-based NPYantagonists. Amino acid-based compounds, which may be mentioned includethose disclosed in international patent applications WO 94/17035, WO97/19911, WO 97/19913, WO 97/19914 or, preferably, WO 99/15498.Preferred amino acid-based NPY antagonists include those that arespecifically disclosed in these patent documents, for example BIBP3226and, especially,(R)—N2-(diphenylacetyl)-(R)—N-[1-(4-hydroxy-phenyl)ethyl]arginine amide(Example 4 of international patent application WO 99/15498).

M1 receptor agonists and compositions containing such inhibitors aredescribed, e.g. in WO2004/087158, WO91/10664.

Suitable M1 receptor antagonists for the purpose of the presentinvention are for example CDD-0102 (Cognitive Pharmaceuticals);Cevimeline (Evoxac) (Snow Brand Milk Products Co. Ltd.); NGX-267(TorreyPines Therapeutics); sabcomeline (GlaxoSmithKline); alvameline (HLundbeck A/S); LY-593093 (Eli Lilly & Co.); VRTX-3 (VertexPharmaceuticals Inc.); WAY-132983 (Wyeth) and CI-101 7/(PD-151832)(Pfizer Inc.).

Acetylcholinesterase inhibitors and compositions containing suchinhibitors are described, e.g. in WO2006/071274, WO2006/070394,WO2006/040688, WO2005/092009, WO2005/079789, WO2005/039580,WO2005/027975, WO2004/084884, WO2004/037234, WO2004/032929, WO03/101458,WO03/091220, WO03/082820, WO03/020289, WO02/32412, WO01/85145,WO01/78728, WO01/66096, WO00/02549, WO01/00215, WO00/15205, WO00/23057,WO00/33840, WO00/30446, WO00/23057, WO00/15205, WO00/09483, WO00/07600,WO00/02549, WO99/47131, WO99/07359, WO98/30243, WO97/38993, WO97/13754,WO94/29255, WO94/20476, WO94/19356, WO93/03034 and WO92/19238.

Suitable acetylcholinesterase inhibitors for the purpose of the presentinvention are for example Donepezil (Eisai Co. Ltd.); rivastigmine(Novartis AG); (−)-phenserine (TorreyPines Therapeutics); ladostigil(Hebrew University of Jerusalem); huperzine A (Mayo Foundation);galantamine (Johnson & Johnson); Memoquin (Universita di Bologna);SP-004 (Samaritan Pharmaceuticals Inc.); BGC-20-1259 (Sankyo Co. Ltd.);physostigmine (Forest Laboratories Inc.); NP-0361 (Neuropharma SA); ZT-1(Debiopharm); tacrine (Warner-Lambert Co.); metrifonate (Bayer Corp.)and INM-176 (Whanln).

NMDA receptor antagonists and compositions containing such inhibitorsare described, e.g. in WO2006/094674, WO2006/058236, WO2006/058059,WO2006/010965, WO2005/000216, WO2005/102390, WO2005/079779,WO2005/079756, WO2005/072705, WO2005/070429, WO2005/055996,WO2005/035522, WO2005/009421, WO2005/000216, WO2004/092189,WO2004/039371, WO2004/028522, WO2004/009062, WO03/010159, WO02/072542,WO02/34718, WO01/98262, WO01/94321, WO01/92204, WO01/81295, WO01/32640,WO1/10833, WO01/10831, WO00/56711, WO00/29023, WO00/00197, WO99/53922,WO99/48891, WO99/45963, WO99/01416, WO99/07413, WO99/01416, WO98/50075,WO98/50044, WO98/10757, WO98/05337, WO97/32873, WO97/23216, WO97/23215,WO97/23214, WO96/14318, WO96/08485, WO95/31986, WO95/26352, WO95/26350,WO95/26349, WO95/26342, WO95/12594, WO95/02602, WO95/02601, WO94/20109,WO94/13641, WO94/09016 and WO93/25534.

Suitable NMDA receptor antagonists for the purpose of the presentinvention are for example Memantine (Merz & Co. GmbH); topiramate(Johnson & Johnson); AVP-923 (Neurodex) (Center for Neurologic Study);EN-3231 (Endo Pharmaceuticals Holdings Inc.); neramexane (MRZ-2/579)(Merz and Forest); CNS-5161 (CeNeS Pharmaceuticals Inc.); dexanabinol(HU-211; Sinnabidol; PA-50211) (Pharmos); EpiCept NP-1 (DalhousieUniversity); indantadol (V-3381; CNP-3381) (Vernalis); perzinfotel(EAA-090, WAY-126090, EAA-129) (Wyeth); RGH-896 (Gedeon Richter Ltd.);traxoprodil (CP-101606), besonprodil (PD-196860, CI-1041) (Pfizer Inc.);CGX-1007 (Cognetix Inc.); delucemine (NPS-1506) (NPS PharmaceuticalsInc.); EVT-101 (Roche Holding AG); acamprosate (Synchroneuron LLC.);CR-3991, CR-2249, CR-3394 (Rottapharm SpA.); AV-101 (4-CI-kynurenine(4-CI-KYN)), 7-chloro-kynurenic acid (7-CI-KYNA) (VistaGen); NPS-1407(NPS Pharmaceuticals Inc.); YT-1006 (Yaupon Therapeutics Inc.); ED-1812(Sosei R&D Ltd.); himantane (hydrochlorideN-2-(adamantly)-hexamethylen-imine) (RAMS); Lancicemine (AR-R-15896)(AstraZeneca); EVT-102, Ro-25-6981 and Ro-63-1908 (Hoffmann-La RocheAG/Evotec).

Furthermore, the present invention relates to combination therapiesuseful for the treatment of atherosclerosis, restenosis or arthritis,administering a QC inhibitor in combination with another therapeuticagent selected from the group consisting of inhibitors of theangiotensin converting enzyme (ACE); angiotensin II receptor blockers;diuretics; calcium channel blockers (CCB); beta-blockers; plateletaggregation inhibitors; cholesterol absorption modulators; HMG-Co-Areductase inhibitors; high density lipoprotein (HDL) increasingcompounds; renin inhibitors; IL-6 inhibitors; antiinflammatorycorticosteroids; antiproliferative agents; nitric oxide donors;inhibitors of extracellular matrix synthesis; growth factor or cytokinesignal transduction inhibitors; MCP-1 antagonists and tyrosine kinaseinhibitors providing beneficial or synergistic therapeutic effects overeach monotherapy component alone.

Angiotensin II receptor blockers are understood to be those activeagents that bind to the AT1-receptor subtype of angiotensin II receptorbut do not result in activation of the receptor. As a consequence of theblockade of the AT1 receptor, these antagonists can, e.g. be employed asantihypertensive agents.

Suitable angiotensin II receptor blockers which may be employed in thecombination of the present invention include AT₁ receptor antagonistshaving differing structural features, preferred are those withnon-peptidic structures. For example, mention may be made of thecompounds that are selected from the group consisting of valsartan (EP443983), losartan (EP 253310), candesartan (EP 459136), eprosartan (EP403159), irbesartan (EP 454511), olmesartan (EP 503785), tasosartan (EP539086), telmisartan (EP 522314), the compound with the designation E-4177 of the formula

the compound with the designation SC-52458 of the following formula

and the compound with the designation the compound ZD-8731 of theformula

or, in each case, a pharmaceutically acceptable salt thereof.

Preferred AT1-receptor antagonists are those agents that have beenapproved and reached the market, most preferred is valsartan, or apharmaceutically acceptable salt thereof.

The interruption of the enzymatic degradation of angiotensin toangiotensin II with ACE inhibitors is a successful variant for theregulation of blood pressure and thus also makes available a therapeuticmethod for the treatment of hypertension.

A suitable ACE inhibitor to be employed in the combination of thepresent invention is, e.g. a compound selected from the group consistingalacepril, benazepril, benazeprilat; captopril, ceronapril, cilazapril,delapril, enalapril, enaprilat, fosinopril, imidapril, lisinopril,moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril andtrandolapril, or in each case, a pharmaceutically acceptable saltthereof.

Preferred ACE inhibitors are those agents that have been marketed, mostpreferred are benazepril and enalapril.

A diuretic is, for example, a thiazide derivative selected from thegroup consisting of chlorothiazide, hydrochlorothiazide,methylclothiazide, and chlorothalidon. The most preferred diuretic ishydrochlorothiazide. A diuretic furthermore comprises a potassiumsparing diuretic such as amiloride or triameterine, or apharmaceutically acceptable salt thereof.

The class of CCBs essentially comprises dihydropyridines (DHPs) andnon-DHPs, such as diltiazem-type and verapamil-type CCBs.

A CCB useful in said combination is preferably a DHP representativeselected from the group consisting of amlodipine, felodipine, ryosidine,isradipine, lacidipine, nicardipine, nifedipine, niguldipine,niludipine, nimodipine, nisoldipine, nitrendipine and nivaldipine, andis preferably a non-DHP representative selected from the groupconsisting of flunarizine, prenylamine, diltiazem, fendiline,gallopamil, mibefradil, anipamil, tiapamil and verapamil, and in eachcase, a pharmaceutically acceptable salt thereof. All these CCBs aretherapeutically used, e.g. as anti-hypertensive, anti-angina pectoris oranti-arrhythmic drugs.

Preferred CCBs comprise amlodipine, diltiazem, isradipine, nicardipine,nifedipine, nimodipine, nisoldipine, nitrendipine and verapamil or, e.g.dependent on the specific CCB, a pharmaceutically acceptable saltthereof. Especially preferred as DHP is amlodipine or a pharmaceuticallyacceptable salt thereof, especially the besylate. An especiallypreferred representative of non-DHPs is verapamil or a pharmaceuticallyacceptable salt, especially the hydrochloride, thereof.

Beta-blockers suitable for use in the present invention includebeta-adrenergic blocking agents (beta-blockers), which compete withepinephrine for beta-adrenergic receptors and interfere with the actionof epinephrine. Preferably, the beta-blockers are selective for thebeta-adrenergic receptor as compared to the alpha-adrenergic receptors,and so do not have a significant alpha-blocking effect. Suitablebeta-blockers include compounds selected from acebutolol, atenolol,betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol,metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol,sotalol and timolol. Where the beta-blocker is an acid or base orotherwise capable of forming pharmaceutically acceptable salts orprodrugs, these forms are considered to be encompassed herein, and it isunderstood that the compounds may be administered in free form or in theform of a pharmaceutically acceptable salt or a prodrug, such as aphysiologically hydrolyzable and acceptable ester. For example,metoprolol is suitably administered as its tartrate salt, propranolol issuitably administered as the hydrochloride salt, and so forth.

Platelet aggregation inhibitors include PLAVIX® (clopidogrel bisulfate),PLETAL® (cilostazol) and aspirin.

Cholesterol absorption modulators include ZETIA® (ezetimibe) and KT6-971(Kotobuki Pharmaceutical Co. Japan).

HMG-Co-A reductase inhibitors (also calledbeta-hydroxy-beta-methylglutaryl-co-enzyme-A reductase inhibitors orstatins) are understood to be those active agents which may be used tolower lipid levels including cholesterol in blood.

The class of HMG-Co-A reductase inhibitors comprises compounds havingdiffering structural features. For example, mention may be made of thecompounds, which are selected from the group consisting of atorvastatin,cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin,rosuvastatin and simvastatin, or in each case, a pharmaceuticallyacceptable salt thereof.

Preferred HMG-Co-A reductase inhibitors are those agents, which havebeen marketed, most preferred is atorvastatin, pitavastatin orsimvastatin, or a pharmaceutically acceptable salt thereof.

HDL-increasing compounds include, but are not limited to, cholesterolester transfer protein (CETP) inhibitors. Examples of CETP inhibitorsinclude JTT7O5 disclosed in Example 26 of U.S. Pat. No. 6,426,365 issuedJul. 30, 2002, and pharmaceutically acceptable salts thereof.

Inhibition of interleukin 6 mediated inflammation may be achievedindirectly through regulation of endogenous cholesterol synthesis andisoprenoid depletion or by direct inhibition of the signal transductionpathway utilizing interleukin-6 inhibitor/antibody, interleukin-6receptor inhibitor/antibody, interleukin-6 antisense oligonucleotide(ASON), gp130 protein inhibitor/antibody, tyrosine kinaseinhibitors/antibodies, serine/threonine kinase inhibitors/antibodies,mitogen-activated protein (MAP) kinase inhibitors/antibodies,phosphatidylinositol 3-kinase (PI3K) inhibitors/antibodies, Nuclearfactor kappaB (NF-κB) inhibitors/antibodies, IκB kinase (IKK)inhibitors/antibodies, activator protein-1 (AP-1) inhibitors/antibodies,STAT transcription factors inhibitors/antibodies, altered IL-6, partialpeptides of IL-6 or IL-6 receptor, or SOCS (suppressors of cytokinesignaling) protein, PPAR gamma and/or PPAR beta/delta activators/ligandsor a functional fragment thereof.

A suitable antiinflammatory corticosteroid is dexamethasone.

Suitable antiproliferative agents are cladribine, rapamycin, vincristineand taxol.

A suitable inhibitor of extracellular matrix synthesis is halofuginone.

A suitable growth factor or cytokine signal transduction inhibitor is,e.g. the ras inhibitor R115777.

A suitable tyrosine kinase inhibitor is tyrphostin.

Suitable renin inhibitors are described, e.g. in WO 2006/116435. Apreferred renin inhibitor is aliskiren, preferably in the form of thehemi-fumarate salt thereof.

MCP-1 antagonists may, e.g. be selected from anti-MCP-1 antibodies,preferably monoclonal or humanized monoclonal antibodies, MCP-1expression inhibitors, CCR2-antagonists, TNF-alpha inhibitors, VCAM-1gene expression inhibitors and anti-C5a monoclonal antibodies.

MCP-1 antagonists and compositions containing such inhibitors aredescribed, e.g. in WO02/070509, WO02/081463, WO02/060900, US2006/670364,US2006/677365, WO2006/097624, US2006/316449, WO2004/056727, WO03/053368,WO00/198289, WO00/157226, WO0/046195, WO0/046196, WO0/046199,WO0/046198, WO0/046197, WO99/046991, WO99/007351, WO98/006703,WO97/012615, WO2005/105133, WO03/037376, WO2006/125202, WO2006/085961,WO2004/024921, WO2006/074265.

Suitable MCP-1 antagonists are, for instance, C-243 (Telik Inc.);NOX-E36 (Noxxon Pharma AG); AP-761 (Actimis Pharmaceuticals Inc.);ABN-912, NIBR-177 (Novartis AG); CC-11006 (Celgene Corp.); SSR-150106(Sanofi-Aventis); MLN-1202 (Millenium Pharmaceuticals Inc.); AGI-1067,AGIX-4207, AGI-1096 (AtherioGenics Inc.); PRS-211095, PRS-211092(Pharmos Corp.); anti-C5a monoclonal antibodies, e.g. neutrazumab (G2Therapies Ltd.); AZD-6942 (AstraZeneca plc.); 2-mercaptoimidazoles(Johnson & Johnson); TEI-E00526, TEI-6122 (Deltagen); RS-504393 (RocheHolding AG); SB-282241, SB-380732, ADR-7 (GlaxoSmithKline); anti-MCP-1monoclonal antibodies (Johnson & Johnson).

Combinations of QC-inhibitors with MCP-1 antagonists may be useful forthe treatment of inflammatory diseases in general, includingneurodegenerative diseases.

Combinations of QC-inhibitors with MCP-1 antagonists are preferred forthe treatment of Alzheimer's disease.

Most preferably the QC inhibitor is combined with one or more compoundsselected from the following group:

PF-4360365, m266, bapineuzumab, R-1450, Posiphen, (+)-phenserine,MK-0752, LY-450139, E-2012, (R)-flurbiprofen, AZD-103, AAB-001(Bapineuzumab), Tramiprosate, EGb-761, TAK-070, Doxofylline,theophylline, cilomilast, tofimilast, roflumilast, tetomilast,tipelukast, ibudilast, HT-0712, MEM-1414, oglemilast, Linezolid,budipine, isocarboxazid, phenelzine, tranylcypromine, indantadol,moclobemide, rasagiline, ladostigil, safinamide, ABT-239, ABT-834,GSK-189254A, Ciproxifan, JNJ-17216498, Fmoc-Ala-Pyrr-CN,Z-Phe-Pro-Benzothiazole, Z-321, ONO-1603, JTP-4819, S-17092, BIBP3226;(R)—N2-(diphenylacetyl)-(R)—N-[1-(4-hydroxyphenyl)ethyl]arginine amide,Cevimeline, sabcomeline, (PD-151832), Donepezil, rivastigmine,(−)-phenserine, ladostigil, galantamine, tacrine, metrifonate,Memantine, topiramate, AVP-923, EN-3231, neramexane, valsartan,benazepril, enalapril, hydrochlorothiazide, amlodipine, diltiazem,isradipine, nicardipine, nifedipine, nimodipine, nisoldipine,nitrendipine, verapamil, amlodipine, acebutolol, atenolol, betaxolol,bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol,nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol,timolol, PLAVIX® (clopidogrel bisulfate), PLETAL® (cilostazol), aspirin,ZETIA® (ezetimibe) and KT6-971, statins, atorvastatin, pitavastatin orsimvastatin; dexamethasone, cladribine, rapamycin, vincristine, taxol,aliskiren, C-243, ABN-912, SSR-150106, MLN-1202 and betaferon.

In particular, the following combinations are considered:

-   -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with Atorvastatin for the treatment and/or        prevention of artherosclerosis,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with immunosuppressive agents, preferably        rapamycin for the prevention and/or treatment of restenosis,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with immunosuppressive agents, preferably        paclitaxel for the prevention and/or treatment of restenosis,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with AChE inhibitors, preferably Donepezil,        for the prevention and/or treatment of Alzheimer's disease,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with interferones, preferably Aronex, for        the prevention and/or treatment of multiple sclerosis,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with interferones, preferably betaferon,        for the prevention and/or treatment of multiple sclerosis,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with interferones, preferably Rebif, for        the prevention and/or treatment of multiple sclerosis    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with Copaxone, for the prevention and/or        treatment of multiple sclerosis,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with dexamethasone, for the prevention        and/or treatment of restenosis,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with dexamethasone, for the prevention        and/or treatment of atherosclerosis,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with dexamethasone, for the prevention        and/or treatment of rheumatid arthritis,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with HMG-Co-A-reductase inhibitors, for the        prevention and/or treatment of restenosis, wherein the        HMG-Co-A-reductase inhibitor is selected from atorvastatin,        cerivastatin, fluvastatin, lovastatin, pitavastatin,        pravastatin, rosuvastatin and simvastatin,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with HMG-Co-A reductase inhibitors, for the        prevention and/or treatment of atherosclerosis wherein the        HMG-Co-A-reductase inhibitor is selected from atorvastatin,        cerivastatin, fluvastatin, lovastatin, pitavastatin,        pravastatin, rosuvastatin and simvastatin,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with HMG-Co-A reductase inhibitors, for the        prevention and/or treatment of rheumatoid arthritis wherein the        HMG-Co-A-reductase inhibitor is selected from atorvastatin,        cerivastatin, fluvastatin, lovastatin, pitavastatin,        pravastatin, rosuvastatin and simvastatin,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with amyloid-beta antibodies for the        prevention and/or treatment of mild cognitive impairment,        wherein the amyloid-beta antibody is Acl-24,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with amyloid-beta antibodies for the        prevention and/or treatment of Alzheimer's disease, wherein the        amyloid-beta antibody is Acl-24,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with amyloid-beta antibodies for the        prevention and/or treatment of neurodegeneration in Down        Syndrome, wherein the amyloid-beta antibody is Acl-24,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with beta-secretase inhibitors for the        prevention and/or treatment of mild cognitive impairment,        wherein the beta-secretase inhibitor is selected from WY-25105,        GW-840736× and CTS-21166,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with beta-secretase inhibitors for the        prevention and/or treatment of Alzheimer's disease, wherein the        beta-secretase inhibitor is selected from WY-25105, GW-840736×        and CTS-21166,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with beta-secretase inhibitors for the        prevention and/or treatment of neurodegeneration in Down        Syndrome, wherein the beta-secretase inhibitor is selected from        WY-25105, GW-840736× and CTS-21166,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with gamma-secretase inhibitors for the        prevention and/or treatment of mild cognitive impairment,        wherein the gamma-secretase inhibitor is selected from        LY-450139, LY-411575 and AN-37124,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with gamma-secretase inhibitors for the        prevention and/or treatment of Alzheimer's disease, wherein the        gamma-secretase inhibitor is selected from LY-450139, LY-411575        and AN-37124,    -   a QC inhibitor, preferably a QC inhibitor of formula (I), more        preferably a QC inhibitor selected from any one of examples        1-30, in combination with gamma-secretase inhibitors for the        prevention and/or treatment of neurodegeneration in Down        Syndrome, wherein the gamma-secretase inhibitor is selected from        LY-450139, LY-411575 and AN-37124.

Such a combination therapy is in particular useful for AD, FAD, FDD andneurodegeneration in Down syndrome as well as atherosclerosis,rheumatoid arthritis, restenosis and pancreatitis.

Such combination therapies might result in a better therapeutic effect(less proliferation as well as less inflammation, a stimulus forproliferation) than would occur with either agent alone.

With regard to the specific combination of inhibitors of QC and furthercompounds it is referred in particular to WO 2004/098625 in this regard,which is incorporated herein by reference.

Pharmaceutical Compositions

To prepare the pharmaceutical compositions of this invention, at leastone compound of formula (I) optionally in combination with at least oneof the other aforementioned agents can be used as the activeingredient(s). The active ingredient(s) is intimately admixed with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques, which carrier may take a wide variety of formsdepending of the form of preparation desired for administration, e.g.,oral or parenteral such as intramuscular. In preparing the compositionsin oral dosage form, any of the usual pharmaceutical media may beemployed. Thus, for liquid oral preparations, such as for example,suspensions, elixirs and solutions, suitable carriers and additivesinclude water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents and the like; for solid oral preparations such as, forexample, powders, capsules, gelcaps and tablets, suitable carriers andadditives include starches, sugars, diluents, granulating agents,lubricants, binders, disintegrating agents and the like. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are obviously employed. If desired, tablets may be sugar coatedor enteric coated by standard techniques. For parenterals, the carrierwill usually comprise sterile water, though other ingredients, forexample, for purposes such as aiding solubility or for preservation, maybe included.

Injectable suspensions may also prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient(s) necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per dosage unit, e.g., tablet, capsule, powder, injection, suppository,teaspoonful and the like, from about 0.03 mg to 100 mg/kg (preferred0.1-30 mg/kg) and may be given at a dosage of from about 0.1-300 mg/kgper day (preferred 1-50 mg/kg per day) of each active ingredient orcombination thereof. The dosages, however, may be varied depending uponthe requirement of the patients, the severity of the condition beingtreated and the compound being employed. The use of either dailyadministration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 500 mg ofeach active ingredient or combinations thereof of the present invention.

The tablets or pills of the compositions of the present invention can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of material can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

This liquid forms in which the compositions of the present invention maybe incorporated for administration orally or by injection include,aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone or gelatin.

The pharmaceutical composition may contain between about 0.01 mg and 100mg, preferably about 5 to 50 mg, of each compound, and may beconstituted into any form suitable for the mode of administrationselected. Carriers include necessary and inert pharmaceuticalexcipients, including, but not limited to, binders, suspending agents,lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.Compositions suitable for oral administration include solid forms, suchas pills, tablets, caplets, capsules (each including immediate release,timed release and sustained release formulations), granules, andpowders, and liquid forms, such as solutions, syrups, elixirs,emulsions, and suspensions. Forms useful for parenteral administrationinclude sterile solutions, emulsions and suspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbetalactose, corn sweeteners, natural and synthetic gums such as acacia,tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodiumbenzoate, sodium acetate, sodium chloride and the like. Disintegratorsinclude, without limitation, starch, methyl cellulose, agar, bentonite,xanthan gum and the like.

The liquid forms in suitable flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

The compounds or combinations of the present invention can also beadministered in the form of liposome delivery systems, such as smallunilamellar vesicles, large unilamellar vesicles, and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids, suchas cholesterol, stearylamine or phosphatidylcholines.

Compounds or combinations of the present invention may also be deliveredby the use of monoclonal antibodies as individual carriers to which thecompound molecules are coupled. The compounds of the present inventionmay also be coupled with soluble polymers as targetable drug carriers.Such polymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamid-ephenol, or polyethyl eneoxidepolyllysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example, polyacticacid, polyepsilon caprolactone, polyhydroxy butyeric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds or combinations of this invention may be administered in anyof the foregoing compositions and according to dosage regimensestablished in the art whenever treatment of the addressed disorders isrequired.

The daily dosage of the products may be varied over a wide range from0.01 to 1.000 mg per mammal per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250 and 500 milligrams of each active ingredient or combinationsthereof for the symptomatic adjustment of the dosage to the patient tobe treated. An effective amount of the drug is ordinarily supplied at adosage level of from about 0.1 mg/kg to about 300 mg/kg of body weightper day. Preferably, the range is from about 1 to about 50 mg/kg of bodyweight per day. The compounds or combinations may be administered on aregimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of disease condition. In addition,factors associated with the particular patient being treated, includingpatient age, weight, diet and time of administration, will result in theneed to adjust dosages.

In a further aspect, the invention also provides a process for preparinga pharmaceutical composition comprising at least one compound of formula(I), optionally in combination with at least one of the otheraforementioned agents and a pharmaceutically acceptable carrier.

The compositions are preferably in a unit dosage form in an amountappropriate for the relevant daily dosage.

Suitable dosages, including especially unit dosages, of the compounds ofthe present invention include the known dosages including unit doses forthese compounds as described or referred to in reference text such asthe British and US Pharmacopoeias, Remington's Pharmaceutical Sciences(Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, ThePharmaceutical Press) (for example see the 31st Edition page 341 andpages cited therein) or the above mentioned publications.

Having described the one or more inventions in detail, it will beapparent that modifications, variations, and equivalent embodiments arepossible without departing the scope of the invention(s) defined in theappended claims. Furthermore, it should be appreciated that all examplesin the present disclosure are provided as non-limiting examples.

EXAMPLES

The following non-limiting examples are provided to further illustratethe present invention(s). It should be appreciated by those of skill inthe art that the techniques disclosed in the examples that followrepresent approaches the inventors have found function well in thepractice of the invention, and thus can be considered to constituteexamples of modes for its practice. However, those of skill in the artshould, in light of the present disclosure, appreciate that changesmight be made in the specific embodiments that are disclosed and stillobtain a like or similar result without departing from the spirit andscope of the invention(s).

Det K_(i) IC₅₀ Ex. Name Structure Weight [M + H]⁺ [μM] [μM] 1 2-cyano(4-ethylphenyl)-3-(3-(5- methyl-1H-imidazol-1- yl)propyl)guanidine

310.40 311.2 0.170 0.62 2 (2-cyano(4- isopropylphenyl)-3-(3-(5-methyl-1H- imidazol-1- yl)propyl)guanidine

324.42 325.4 0.091 0.55 3 2-cyano(2,3- dihydrobenzo[b][1,4]dioxin-7-yl)-3-(3-(5- methyl-1H-imidazol-1- yl)propyl)guanidine

340.37 341.1 0.092 0.53 4 2-cyano(4- cyanophenyl)-3-(3-(5-methyl-1H-imidazol-1- yl)propyl)guanidine

307.35 308.1 0.186 1.05 5 2-cyano(3,4,5- trimethoxyphenyl)-3-(3-(5-methyl-1H- imidazol-1- yl)propyl)guanidine

372.42 373.1 0.061 0.67 6 2-cyano(4- ethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1- yl)propyl)guanidine

326.39 327.4 0.091 1.09 7 2-cyano(3-(5-methyl- 1H-imidazol-1-yl)propyl)-3-(3,4- dimethylphenyl)guanidine

310.39 311.4 0.072 0.68 8 (3-(5-methyl-1H- imidazol-1-yl)propyl)-2-cyano-3- mesitylguanidine

324.42 325.3 0.106 0.624 9 (3-(5-methyl-1H- imidazol-1-yl)propyl)-2-cyano- 3-(biphenyl-4- yl)guanidine

358.43 359.4 0.065 0.77 10 (3-(5-methyl-1H- imidazol-1-yl)propyl)-2-cyano- 3-(naphthalen-2- yl)guanidine

332.40 333.5 0.094 1.09 11 (3-(5-methyl-1H- imidazol-1-yl)propyl)-2-cyano-3- (naphthalen-1- yl)guanidine

332.40 333.4 0.103 0.61 12 (3-(5-methyl-1H- imidazol-1- yl)propyl)-3-(benzo[c][1,2,5] thiadiazol-6-yl)-2- cyanoguanidine

340.41 341.1 0.132 1.34 13 (3-(5-methyl-1H- imidazol-1-yl)propyl)-3-(3,4-dichlorophenyl)- 2-cyanoguanidine

351.23 351.5 0.102 0.67 14 (benzo[d][1,3]dioxol-6- yl)-2-cyano-3-(3-(5-methyl-1H-imidazol-1- yl)propyl)guanidine

326.35 327.1 0.110 0.59 15 2-cyano(4- methoxyphenyl)-3-(3- (5-methyl-1H-imidazol-1- yl)propyl)guanidine

312.37 313.2 0.074 0.79 16 2-cyano(3,5- dimethoxyphenyl)-3-(3-(5-methyl-1H- imidazol-1- yl)propyl)guanidine

342.40 343.0 0.125 0.726 17 2-cyano(4- ethoxyphenyl)-3-(3-(4-methyl-1H-imidazol-1- yl)propyl)guanidine

326.39 327.4 1.33 5.69 18 2-cyano(3,5- dimethoxyphenyl)-3-(3-(4-methyl-1H- imidazol-1- yl)propyl)guanidine

342.39 343.3 12.3 19 2-cyano(2,3- dihydrobenzo[b][1,4]dioxin-7-yl)-3-(3-(4- methyl-1H-imidazol-1- yl)propyl)guanidine

340.37 341.2 1.65 9.47 20 2-cyano(mesityl)-3-(3- (4-methyl-1H-imidazol-1- yl)propyl)guanidine

324.42 325.3 1.28 8.5 21 2-cyano(4- isopropylphenyl)-3-(3- (4-methyl-1H-imidazol-1- yl)propyl)guanidine

324.42 325.3 2.31 14.9 22 2-cyano(4- ethylphenyl)-3-(3-(4-methyl-1H-imidazol-1- yl)propyl)guanidine

310.39 311.2 2.37 13.9 23 2-cyano(3-(4-methyl- 1H-imidazol-1-yl)propyl)-3- (naphthalen-1- yl)guanidine

332.40 333.4 1.69 13.8 24 (benzo[c][1,2,5]thiadiazol-6-yl)-2-cyano-3-(3- (4-methyl-1H- imidazol-1- yl)propyl)guanidine

340.40 341.3 2.21 12.2 25 2-cyano(3,4,5- trimethoxyphenyl)-3-(3-(4-methyl-1H- imidazol-1- yl)propyl)guanidine

372.42 373.3 0.911 6.78 26 2-cyano(4- cyanophenyl)-3-(3-(4-methyl-1H-imidazol-1- yl)propyl)guanidine

307.35 308.4 30.1 27 (3,4-dichlorophenyl)-2- cyano-3-(3-(4-methyl-1H-imidazol-1- yl)propyl)guanidine

351.23 353.2 2.6 17.1 28 2-cyano(4- methoxyphenyl)-3-(3- (4-methyl-1H-imidazol-1- yl)propyl)guanidine

312.36 313.3 2.03 14.4 29 2-cyano-1-[3-(4- methyl-1H-imidazol-1-yl)propyl]-4- phenylbenzene-1- guanidine

358.43 359.3 1.58 10.4 30 2-cyano(3-(4-methyl- 1H-imidazol-1-yl)propyl)-3- (naphthalen-2- yl)guanidine

332.40 333.5 1.87 12.4General Synthesis Description

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Sodium cyanamide (1.0 eq.) and the corresponding isothiocyanate (1.0eq.) were dissolved in 10 mL of dry ethanol. The mixture was stirredunder reflux for 3 h. After cooling down to room temperature 5 or 9 (1.0eq.), and N¹-((ethylimino)methylen)-N³,N³-dimethylpropan-1,3-diaminehydrochloride (1.2 eq.) and 5 mL of dimethylformamide were added and themixture was stirred at room temperature for 3 h. The solvent was removedand the remaining residue was taken up in 30 mL of chloroform. Theorganic layer was washed one times by means of water, dried over Na₂SO₄,filtered and than the solvent was removed. Purification of the productswas done by means of flash-chromatography utilizing basic aluminum oxideand a gradient consisting of chloroform and methanol or was purified bymeans of semi-preparative HPLC.

Detailed Synthesis Description

Synthesis of 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5)

3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5)4-methyl-1-trityl-1H-imidazole (2)

4-methyl-1H-imidazole (1) (36.53 mmol, 1 eq) of was dissolved in 120 mLof dimethylformamide, triethylamine (73.06 mmol, 2 eq.) andchlorotriphenylmethane (40.1 mmol, 1.1 eq) where added. The mixture wasstirred for 3.5 h. The precipitate filtered off and was washed by meansof ice-cooled dimethylformamide (2×50 mL) and water (2×50 mL). Afterremoval of the solvent the remaining product was dried over P₄O₁₀.

Yield: 10.65 g (98.2%). The product was used without furtherpurification.

1-Trityl-3-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-1,4-dimethyl-1H-imidazol-3-iumbromide (3)

4-Methyl-1-trityl-1H-imidazole (i.e 32.85 mmol, 1 eq.) was suspended inacetonitrile (10 mL) and 2-(3-bromopropyl)isoindoline-1,3-dione (32.85mmol, 1 eq.) was added. The mixture was kept under reflux over night.The organic solvent was removed

Purification was done by flash-chromatography using silica gel and aCHCl₃/MeOH-gradient.

Yield: 10.65 g (63.44%).

2-(3-(5-methyl-1H-imidazol-1-yl)propyl)isoindoline-1,3-dione (4)

1-Trityl-3-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-1,4-dimethyl-1H-imidazol-3-iumbromide (i.e. 7.86 mmol) was dissolved in a stirred solution containingmethanol (20 mL) and trifluoracetic acid (4 mL). The mixture was keptunder reflux over night. After that the solvent was removed by means ofreduced pressure and the remaining oil was purified byflash-chromatography using silica gel and a CHCl₃/MeOH-gradient.

Yield: 2.05 g (97.0%).

3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5)

2-(3-(5-methyl-1H-imidazol-1-yl)propyl)isoindoline-1,3-dione (i.e. 8.92mmol, 1 eq.) and hydzine monohydrate (17.84 mmol, 2 eq.) were dissolvedin dry EtOH (50 mL). The mixture was kept under reflux over night, thenmixture was concentrated down to a volume of 25 mL. After thathydrochloric acid (conc., 55 mL) was added and the mixture was heated upto 50° C. for and kept at this temperature for 30 min. The formedprecipitate was filtered off. The filtrate was cooled down to 0° C. andsolid NaOH was added until a final pH-value of 10-12 is reached. Theaqueous solution was extracted by means of CHCl₃ (3×50 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and the solvent wasremoved. The product was purified by means of flash-chromatography usingsilica gel and a CHCl₃/MeOH-gradient.

Yield: 0.74 g (60%), viscous oil

Yield over all steps: 36.3%

¹H-NMR (CDCl₃, 499.78 MHz): δ 1.79-1.847 (m, 2H); 2.179 (s, 3H);2.694-2.721 (m, 2H); 3.891-3.920 (m, 2H); 6.731 (s, H); 7.240 (s,solv.); 7.380 (s; H); ESI-MS m/z: 140.3 (M+H)⁺, 279.4 (2M+H)⁺; HPLC(λ=214 nm) rt: dead time (100%)

3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9)

2-(3-(4/5-methyl-1H-imidazol-1-yl)propyl)isoindoline-1,3-dione (7)

4-methyl-1H-imidazole (6) (36.53 mmol, 1 eq) and sodium hydride (60% inmineral oil, 36.53 mmol, 1.0 eq.) were dissolved in 80 mL ofdimethylformamide. The mixture was stirred at room temperature for 2 huntil the formation of hydrogen gas deceased.2-(3-bromopropyl)isoindoline-1,3-dione (34.70 mmol, 0.95 eq.) was addedand the mixture was stirred at 90° C. overnight. The solvent was removedand the remaining residue was purified by means of flash-chromatographyusing silica gel and a CHCl₃/MeOH-gradient.

Yield: 6.1 g (62.0%) of a mixture of2-(3-(4-methyl-1H-imidazol-1-yl)propyl)isoindoline-1,3-dione and2-(3-(5-methyl-1H-imidazol-1-yl)propyl)isoindoline-1,3-dione

2-(3-(4-methyl-1H-imidazol-1-yl)propyl)isoindoline-1,3-dione (8)

A mixture consisting of2-(3-(4-methyl-1H-imidazol-1-yl)propyl)isoindoline-1,3-dione and2-(3-(5-methyl-1H-imidazol-1-yl)propyl)isoindoline-1,3-dione (7) (22.65mmol, 1 eq.) and tritylchlorid (13.6 mmol, 0.6 eq.) were dissolved in 40mL of dichloromethane and kept at a temperature of 0° C. for 10 min and1.5 h at room temperature. The solvent was removed and pressure theremaining solid was purified by means of flash-chromatography usingsilica gel and a CHCl₃/MeOH-gradient.

Yield: 0.92 g (15.1%)

3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9)

2-(3-(4-methyl-1H-imidazol-1-yl)propyl)isoindoline-1,3-dione (3.42 mmol,1 eq.) and hydrazine monohydrate (6.84 mmol, 2 eq.) were dissolved in 20mL of ethanol and the mixture was stirred for 12 h under reflux. Themixture was kept under reflux over night, then mixture was concentrateddown to a volume of 25 mL. After that hydrochloric acid (conc., 55 mL)was added and the mixture was heated up to 50° C. for and kept at thistemperature for 30 min. The formed precipitate was filtered off. Thefiltrate was cooled down to 0° C. and solid NaOH was added until a finalpH-value of 10-12 is reached. The aqueous solution was extracted bymeans of CHCl₃ (3×50 mL). The combined organic layers were dried overNa₂SO₄, filtered and the solvent was removed. The product was purifiedby means of flash-chromatography using silica gel and aCHCl₃/MeOH-gradient containing aqueous ammonia (2% v/v).

Yield: 0.31 g (65.1%).

¹H-NMR (CDCl₃, 499.78 MHz): δ 1.819-1.874 (m, 2H); 2.188 (s, 3H);2.699-2.712 (m, 2H); 3.910-3.948 (m, 2H); 6.594 (s, H); 7.240 (s,solv.); 7.328 (s; H); ESI-MS m/z: 140.3 (M+H)⁺, 279.4 (2M+H)⁺; HPLC(λ=214 nm) rt: dead time (100%)

Semi-Preparative HPLC-Method

The system consisted of Merck-Hitachi device (model LaChrom) equippedwith a SP250/21 Luna® 100-7 C18 semi-preparative column (Phenomenex.length: 250 mm, diameter: 21 mm).

The compounds were purified using a gradient at a flow rate of 6 mL/min;whereby eluent (A) was acetonitrile, eluent (B) was water, bothcontaining 0.1% (v/v) trifluoro acetic acid applying the followinggradient: 0 min-40 min. 40-95% (A)

Synthesis of Examples Example 12-Cyano(4-ethylphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine

The compound was synthesized starting from1-ethyl-4-isothiocyanatobenzene (0.24 g, 1.5 mmol) and3-(5-Methyl-1H-imidazol-1-yl)propan-1-amine (0.20 g, 1.5 mmol) asdescribed above.

Yield: 0.45 g (96.7%). ¹H NMR: (CDCl₃) δ 1.16-1.20 (m, 3H); 2.08-2.13(br m, 2H); 2.27 (s, 3H); 2.55-2.60 (m, 2H); 3.39-3.44 (m, 2H);4.18-4.22 (m, 2H); 6.54-6.57 (m, H); 6.93 (s, H); 7.11-7.16 (br m, 4H);8.06 (s, H); 9.13 (s, H); MS m/z 311.2 (M+H)⁺; HPLC (λ=214 nm, [C]): rt9.07 min (99.6%).

Example 22-Cyano(4-isopropylphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-guanidine

The compound was synthesized starting from1-isopropyl-4-isothiocyanatobenzene (0.27 g, 1.5 mmol) and3-(5-Methyl-1H-imidazol-1-yl)propan-1-amine (0.20 g, 1.5 mmol) asdescribed above.

Yield: 0.44 g (90.0%). ¹H NMR: (CDCl₃) δ 1.18 (s, 3H); 1.20 (s, 3H);2.11-2.13 (m, 2H); 2.29 (s, 3H); 2.81-2.88 (br m; H); 3.42-3.47 (m, 2H);4.23-4.27 (m, 2H); 6.59-6.62 (m, H); 6.97 (s, 1H); 7.14-7.19 (m, 4H);8.09 (s, H); 9.39 (s, H); MS m/z 325.4 (M+H)⁺; HPLC (λ=214 nm, [C]): rt10.31 min (99.9%).

Example 32-Cyano(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine

The compound was synthesized starting from2,3-dihydro-6-isothiocyanato-benzo[b][1,4]dioxine (0.29 g, 1.5 mmol) and3-(5-Methyl-1H-imidazol-1-yl)propan-1-amine (0.20 g, 1.5 mmol) asdescribed above.

Yield: 0.50 g (99.0%). ¹H NMR: (DMSO-d₆) δ 1.80-1.87 (br m, 2H); 2.13(s, 3H); 3.11-3.15 (m, 2H); 3.82-3.86 (m, 2H); 4.22 (s, 4H); 6.59 (s,H); 6.65-6.66 (m, H); 6.67-6.68 (m, H); 6.72-6.73 (m, H); 6.81-6.83 (m,H); 8.30 (s, H); 8.79 (s, H); MS m/z 341.1 (M+H)⁺; HPLC (λ=214 nm, [C]):rt 8.30 min (99.4%).

Example 42-Cyano(4-cyanophenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-guanidine

The compound was synthesized starting from 4-isothiocyanatobenzonitrile(0.24 g, 1.5 mmol) and 3-(5-Methyl-1H-imidazol-1-yl)propan-1-amine (0.20g, 1.5 mmol) as described above.

Yield: 0.29 g (63.0%). ¹H NMR: (DMSO-d₆) δ 1.87-1.94 (m, 2H); 2.14 (s,3H); 3.21-3.25 (m, 2H); 3.88-3.91 (m, 2H); 6.60 (s, H), 7.38-7.40 (m,2H); 7.51 (s, 1H); 7.75-7.78 (m, 2H); 8.30 (s, H); 8.45 (s, H) MS m/z308.1 (M+H)⁺; HPLC (λ=214 nm, [C]): rt 7.75 min (99.15%).

Example 52-Cyano(3,4,5-trimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-guanidine

The compound was synthesized starting from5-isothiocyanato-1,2,3-trimethoxybenzene (0.099 g, 0.44 mmol) and3-(5-Methyl-1H-imidazol-1-yl)propan-1-amine (0.20 g, 1.5 mmol) asdescribed above.

Yield: 0.13 g (80.0%). ¹H NMR: (CDCl₃) δ 2.15-2.19 (m, 2H); 2.32 (s,3H); 3.44-3.48 (m, 2H); 3.75 (s, 3H); 3.82 (s, 6H); 4.26-4.30 (m, 2H);6.53 (s, H); 7.01 (s, H); 7.08-7.13 (m, H); 7.97 (s, H); 9.54 (s, H); MSm/z 373.1 (M+H)⁺; HPLC (λ=214 nm, [C]): rt 7.69 min (99.05%).

Example 62-Cyano(4-ethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-guanidine

The compound was synthesized starting from1-isothiocyanato-4-methoxybenzene (0.25 g, 1.5 mmol) and3-(5-Methyl-1H-imidazol-1-yl)propan-1-amine (0.20 g, 1.5 mmol) asdescribed above.

Yield: 0.49 g (99.0%). ¹H NMR: (CDCl₃) δ 1.34-1.38 (m, 3H); 2.09-2.12(m, 2H); 2.29 (s, 3H); 3.37-3.42 (br m, 2H); 3.93-3.98 (m, 2H);4.19-4.22 (m, 2H); 6.51-6.53 (m, H); 6.80-6.83 (m, 2H); 6.96 (s, H);7.13-7.15 (m, 2H); 7.81 (s, H); 9.24 (s, H). MS m/z 327.4 (M+H)⁺; HPLC(λ=214 nm, [C]): rt 8.15 min (100%).

Example 72-Cyano(3-(5-methyl-1H-imidazol-1-yl)propyl)-3-(3.4-dimethylphenyl)-guanidine

The compound was synthesized starting from4-isothiocyanato-1,2-dimethylbenzene (0.36 g, 2.2 mmol) and3-(5-Methyl-1H-imidazol-1-yl)propan-1-amine (0.20 g, 1.5 mmol) asdescribed above.

Yield: 0.042 g (7.5%); mp: 154.0-156.0° C.; ¹H NMR: δ (CD₃DO) δ2.05-2.12 (m; 2H); 2.26 (s; 3H); 2.27 (s; 3H); 2.36-2.37 (m; 3H);3.30-3.34 (m; 2H); 4.16-4.20 (m; 2H); 6.95-6.96 (m; H); 6.97 (s; H);7.17-7.19 (m; H); 7.31 (s; H); 8.86 (s; H); MS m/z 311.4 (M+H)⁺;ESI-FTICR-MS: m/z 311.19760 ([M+H]⁺; calc. for C₁₇H₂₃N₆ ⁺311.19787);(λ=214 nm, [A]): rt 22.93 min (99.3%)

Example 8(3-(5-Methyl-1H-imidazol-1-yl)propyl)-2-cyano-3-mesitylguanidine

The compound was synthesized starting from2-isothiocyanato-1,3,5-trimethylbenzene (0.266 g, 1.5 mmol) and3-(5-Methyl-1H-imidazol-1-yl)propan-1-amine (0.20 g, 1.5 mmol) asdescribed above.

Yield: 0.36 g (73.3%); ¹H NMR: δ (CDCl₃) δ 1.86-1.93 (m; 2H); 2.12 (s;3H); 2.18 (s, 6H); 2.28 (s; 3H); 3.19-3.24 (m; 2H); 3.78-3.82 (m; 2H);4.43 (br s, H); 6.67 (s; H); 6.74 (s; H); 6.95 (s, 2H); 7.26 (s; H); MSm/z 325.3 (M+H)⁺; HPLC (λ=214 nm, [B]): rt 9.41 min (100%)

Example 9(3-(5-methyl-1H-imidazol-1-yl)propyl)-2-cyano-3-(biphenyl-4-yl)guanidine

The compound was synthesized starting from1-isothiocyanato-4-phenylbenzene (0.152 g, 0.72 mmol) and3-(5-Methyl-1H-imidazol-1-yl)propan-1-amine (0.10 g, 0.72 mmol) asdescribed above.

Yield: 0.090 g (40.0%); ¹H NMR: (DMSO-d₆) δ 1.83-1.90 (m, 2H); 2.12 (s,3H); 3.15-3.20 (m, 2H); 3.84-3.88 (m, 2H); 6.58 (s, H); 7.28-7.33 (br m,4H); 7.40-7.44 (m, 2H); 7.50 (s, H); 7.61-7.64 (m, 4H); 9.07 (s, H). MSm/z 359.4 (M+H)⁺; HPLC (λ=214 nm, [C]): rt 14.19 min (99.3%)

Example 10(3-(5-methyl-1H-imidazol-1-yl)propyl)-2-cyano-3-(naphthalen-2-yl)guanidine

The compound was synthesized starting from 2-isothiocyanatonaphthalene(0.185 g, 1.0 mmol) and 3-(5-Methyl-1H-imidazol-1-yl)propan-1-amine(0.139 g, 1.0 mmol) as described above.

Yield: 0.17 g (41.0%); ¹H NMR: (DMSO-d₆) δ 1.84-1.91 (br m, 2H); 2.12(s, 3H); 3.13-3.21 (m, 2H); 3.85-3.89 (m, 2H); 6.60 (s, H); 7.29-7.30(m, H); 7.35-7.38 (m, 2H); 7.41-7.49 (br m, 2H); 7.54 (s, H); 7.68 (s,H); 7.81-7.87 (br m, 3H); 9.20 (s, H). MS m/z 333.5 (M+H)⁺; HPLC (λ=214nm, [C]): rt 12.03 min (97.7%)

Example 11(3-(5-Methyl-1H-imidazol-1-yl)propyl)-2-cyano-3-(naphthalen-1-yl)guanidine

The compound was synthesized starting from 1-isothiocyanatonaphthalene(0.278 g, 1.5 mmol) and 3-(5-Methyl-1H-imidazol-1-yl)propan-1-amine(0.20 g, 1.5 mmol) as described above.

Yield: 0.33 g (66.7%). ¹H NMR: (500 MHz, DMSO-d₆) δ 1.81-1.83 (m, 2H);2.09 (s, 3H); 3.13-3.14 (m, 2H); 3.78-3.81 (m, 2H); 6.59 (s, H); 6.86(br s, H); 7.38-7.40 (m, H); 7.47 (s, H); 7.51-7.60 (br m, 3H);7.84-7.86 (m, H); 7.90-7.91 (m, H); 7.97-7.99 (m, H); 9.23 (s, H). MSm/z 333.4 (M+H)⁺; HPLC (λ=214 nm, [B]): rt 8.78 min (99.1%)

Example 12(3-(5-methyl-1H-imidazol-1-yl)propyl)-3-(benzo[c][1,2,5]thiadiazol-6-yl)-2-cyanoguanidine

The compound was synthesized starting from5-isothiocyanatobenzo[c][1,2,5]thiadiazole (0.290 g, 1.5 mmol) and3-(5-Methyl-1H-imidazol-1-yl)propan-1-amine (0.20 g, 1.5 mmol) asdescribed above.

Yield: 0.27 g (52.9%). ¹H NMR: (DMSO-d₆) δ 1.86-1.93 (m, 2H); 2.13 (s,3H); 3.20-3.24 (m, 2H); 3.86-3.90 (m, 2H); 6.58 (s, H); 7.50 (s, H);7.61-7.63 (m, H); 7.65-7.67 (m, H); 7.79 (s, H); 7.99-8.01 (m, H); 9.47(br s, H). MS m/z 341.1 (M+H)⁺; HPLC (λ=214 nm, [C]): rt 8.88 min (100%)

Example 13(3-(5-Methyl-1H-imidazol-1-yl)propyl)-3-(3,4-dichlorophenyl)-2-cyanoguanidine

The compound was synthesized starting from1,2-dichloro-4-isothiocyanatobenzene (0.16 g, 0.8 mmol) and3-(5-Methyl-1H-imidazol-1-yl)propan-1-amine (0.14 g, 1.0 mmol) asdescribed above.

Yield: 0.22 g (78.5%). ¹H NMR: (DMSO-d₆) δ 1.83-1.87 (m, 2H); 2.12 (s,3H); 3.14-3.18 (m, 2H); 3.83-3.87 (m, 2H); 6.58 (s, H); 7.20-7.23 (m,H); 7.46-7.49 (m, 3H); 7.54-7.56 (m, H); 9.17 (s, H). MS m/z 351.5(M+H)⁺; HPLC (λ=214 nm, [B]): rt 10.67 min (97.8%)

Example 14(Benzo[d][1,3]dioxol-6-yl)-2-cyano-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine

The compound was synthesized starting from5-isothiocyanatobenzo[d][1,3]dioxole (0.14 g, 0.80 mmol) and3-(5-Methyl-1H-imidazol-1-yl)propan-1-amine (0.14 g, 1.0 mmol) asdescribed above.

Yield: 0.21 g (81.2%). ¹H NMR: δ (CDCl₃) δ 1.91-1.98 (m, 2H); 2.15 (s,3H); 3.22-3.27 (m, 2H); 3.82-3.85 (m, 2H); 4.92 (br s, H); 6.01 (s, 2H);6.63-6.68 (br m, 2H); 6.79-6.81 (m, H); 7.32 (s, H); 7.38 (s, H). MS m/z327.1 (M+H)⁺; HPLC (λ=214 nm, [B]): rt 7.42 min (98.5%)

Example 152-Cyano(4-methoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine

The compound was synthesized starting from1-isothiocyanato-4-methoxybenzene (0.17 g, 1.0 mmol) and3-(5-Methyl-1H-imidazol-1-yl)propan-1-amine (0.17 g, 1.2 mmol) asdescribed above.

Yield: 0.30 g (96.3%). ¹H NMR: (CDCl₃) δ 1.90-1.99 (br m, 2H); 2.14 (s,3H); 3.23-3.27 (m, 2H); 3.80 (s, 3H); 3.82-3.87 (m, 2H); 4.75 (br s, H);6.67 (s, H), 6.90-6.94 (m, 2H); 7.08-7.11 (m, 2H); 7.22-7.26 (m, H+Sol); 7.29 (s, H). MS m/z 313.2 (M+H)⁺; HPLC (λ=214 nm, [B]): rt 7.58min (99.0%)

Example 162-Cyano-(3,5-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine

The compound was synthesized starting from1-isothiocyanato-3,5-dimethoxybenzene (0.293 g, 1.5 mmol) and3-(5-Methyl-1H-imidazol-1-yl)propan-1-amine (0.20 g, 1.5 mmol) asdescribed above.

Yield: 0.35 g (68.0%); ¹H NMR: (CDCl₃) δ 1.92-1.99 (m; 2H); 2.15 (s;3H); 3.25-3.30 (m, 2H); 3.76 (s, 6H); 3.81-3.86 (m; 2H); 5.20 (br s, H);6.30 (s; 2H); 6.37 (s; H); 6.68 (s, H); 7.31 (s, H); 7.46 (s; H); MS m/z343.0 (M+H)⁺; HPLC (λ=214 nm, [B]): rt 9.87 min (99.0%)

Example 172-cyano(4-ethoxyphenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)-guanidine

The compound was synthesized starting from1-ethoxy-4-isothiocyanatobenzene (0.108 g, 0.60 mmol) and3-(4-Methyl-1H-imidazol-1-yl)propan-1-amine (0.084 g, 0.60 mmol) asdescribed above.

Yield: 0.15 g (76.7%). ¹H NMR (DMSO-d6): δ 1.29-1.33 (m, 3H); 1.83-1.90(m, 2H); 2.05 (s, 3H); 3.08-3.13 (m, 2H); 3.84-3.87 (m; 2H); 3.97-4.03(m; 2H); 6.83 (s, H); 6.87-6.91 (m; 3H); 7.08-7.12 (m; 2H); 7.45 (s; H);8.77 (s, H). MS m/z 327.4 (M+H)⁺; HPLC (λ=214 nm, [C]): rt 8.44 min(96.9%)

Example 182-cyano(3,5-dimethoxyphenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)-guanidine

The compound was synthesized starting from1-isothiocyanato-3,5-dimethoxybenzene (0.117 g, 0.60 mmol) and3-(4-Methyl-1H-imidazol-1-yl)propan-1-amine (0.084 g, 0.60 mmol) asdescribed above.

Yield: 0.18 g (87.6%). ¹H NMR (DMSO-d₆): δ 1.96-2.02 (m, 2H); 2.15 (s,3H); 3.22-3.29 (m, 2H); 3.77 (s, 6H); 3.83-3.90 (m, 2H); 5.16 (br s, H);6.30-6.31 (m, 2H); 6.37-6.38 (m, H); 6.57 (s, H); 7.30 (s, H); 7.41 (s,H). MS m/z 343.3 (M+H)⁺; HPLC (λ=214 nm, [C]): rt 8.22 min (99.3%)

Example 192-cyano(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine

The compound was synthesized starting from2,3-dihydro-6-isothiocyanato-benzo[b][1,4]dioxine (0.116 g, 0.60 mmol)and 3-(4-Methyl-1H-imidazol-1-yl)propan-1-amine (0.084 g, 0.60 mmol) asdescribed above.

Yield: 0.14 g (72.8%). ¹H NMR (DMSO-d₆): δ 1.82-1.89 (m, 2H); 2.05 (s,3H); 3.07-3.12 (m, 2H); 3.84-3.87 (m, 2H); 4.22 (s, 4H); 6.64-6.66 (m,H); 6.67 (s, H); 6.72-6.73 (m, 2H); 6.81-6.83 (m, H); 7.45 (s, H)); 8.77(s, H). MS m/z 341.2 (M+H)⁺; HPLC (λ=214 nm, [C]): rt 8.64 min (100%)

Example 202-cyano(mesityl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine

The compound was synthesized starting from2-isothiocyanato-1,3,5-trimethylbenzene (0.106 g, 0.60 mmol) and3-(4-Methyl-1H-imidazol-1-yl)propan-1-amine (0.084 g, 0.60 mmol) asdescribed above.

Yield: 0.088 g (45.2%). ¹H NMR (DMSO-d₆): δ 1.80-1.84 (m, 2H); 2.04 (s,3H); 2.09 (s, 6H); 2.23 (s, 3H); 3.04-3.06 (m, 2H); 3.80-3.84 (m, 2H);6.59 (br s, H); 6.80 (s, H); 6.91 (s, 2H); 7.42 (s, H); 8.42 (s, H). MSm/z 325.2 (M+H)⁺; HPLC (λ=214 nm, [C]): rt 10.05 min (98.6%)

Example 212-cyano(4-isopropylphenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)-guanidine

The compound was synthesized starting from1-isopropyl-4-isothiocyanatobenzene (0.106 g, 0.60 mmol) and3-(4-Methyl-1H-imidazol-1-yl)propan-1-amine (0.084 g, 0.60 mmol) asdescribed above.

Yield: 0.17 g (87.3%). ¹H NMR (CDCl₃): δ 1.23 (s, 3H); 1.25 (s, 3H);1.95-2.00 (m, 2H); 2.16 (s, 3H); 2.88-2.95 (m, H); 3.21-3.26 (m, 2H);3.86-3.89 (m, 2H); 4.89 (br s, H); 6.57 (s, H); 7.07-7.09 (m, 2H);7.26-7.32 (br m, 3H). MS m/z 325.3 (M+H)⁺; HPLC (λ=214 nm, [C]): rt12.75 min (100%)

Example 222-cyano(4-ethylphenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine

The compound was synthesized starting from1-ethyl-4-isothiocyanatobenzene (0.100 g, 0.60 mmol) and3-(4-Methyl-1H-imidazol-1-yl)propan-1-amine (0.084 g, 0.60 mmol) asdescribed above.

Yield: 0.17 g (91.2%). ¹H NMR (CDCl₃): δ 1.21-1.25 (m, 3H); 1.94-2.01(m, 2H); 2.15 (s, 3H); 2.62-2.68 (m, 2H); 3.21-3.26 (m, 2H); 3.85-3.89(m, 2H); 4.91 (br s, H); 6.56 (s, H); 7.06-7.09 (m, 2H); 7.23 (s, H);7.25 (s, H); 7.31 (s, H); 7.39 (s, H). MS m/z 311.2 (M+H)⁺; HPLC (λ=214nm, [C]): rt 11.23 min (100%)

Example 232-cyano(3-(4-methyl-1H-imidazol-1-yl)propyl)-3-(naphthalen-1-yl)-guanidine

The compound was synthesized starting from 1-isothiocyanatonaphthalene(0.111 g, 0.60 mmol) and 3-(4-Methyl-1H-imidazol-1-yl)propan-1-amine(0.084 g, 0.60 mmol) as described above.

Yield: 0.15 g (75.2%). ¹H NMR (DMSO-d₆): δ 1.82-1.86 (m, 2H); 2.04 (s,3H); 3.09-3.11 (m, 2H); 3.79-3.83 (m, 2H); 6.79 (s, H); 6.86 (br s, H);7.37-7.40 (m, 2H); 7.51-7.60 (br m, 3H); 7.83-7.85 (m; 2H); 7.89-7.99(m, H); 9.20 (s, H). MS m/z 333.4 (M+H)⁺; HPLC (λ=214 nm, [C]): rt 10.72min (100%)

Example 24(benzo[c][1,2,5]thiadiazol-6-yl)-2-cyano-3-(3-(4-methyl-1H-imidazol-1-yl)-propyl)-guanidine

The compound was synthesized starting from5-isothiocyanatobenzo[c][1,2,5]thiadiazole (0.139 g, 0.72 mmol) and3-(4-Methyl-1H-imidazol-1-yl)propan-1-amine (0.10 g, 0.72 mmol) asdescribed above.

Yield: 0.060 g (24.5%). ¹H NMR (DMSO-d₆, 500 MHz): δ 1.93-1.95 (m, 2H);2.05 (s, 3H); 3.19-3.23 (m, 2H); 3.91-3.94 (m, 2H); 6.86 (s; H); 7.49(s, H); 7.63-7.66 (m, H); 7.67-7.69 (m, H); 7.81 (s, H); 8.03-8.05 (m,H); 9.48 (s, H). MS m/z 341.3 (M+H)⁺; HPLC (λ=214 nm, [C]): rt 8.77 min(97.7%)

Example 252-cyano(3,4,5-trimethoxyphenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)-guanidine

The compound was synthesized starting from5-isothiocyanato-1,2,3-trimethoxybenzene (0.162 g, 0.72 mmol) and3-(4-Methyl-1H-imidazol-1-yl)propan-1-amine (0.10 g, 0.72 mmol) asdescribed above.

Yield: 0.110 g (41.0%). ¹H NMR (CDCl₃): δ 1.95-2.01 (m, 2H); 2.14 (s,3H); 3.22-3.27 (m, 2H); 3.82 (s, 9H); 3.86-3.88 (m, 2H); 5.03 (br s, H);6.41 (s, 2H); 6.56 (s, H); 7.28 (s, H); 7.46 (s, H). MS m/z 373.3(M+H)⁺; HPLC (λ=214 nm, [C]): rt 8.64 min (100%)

Example 262-cyano(4-cyanophenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine

The compound was synthesized starting from 4-isothiocyanatobenzonitrile(0.115 g, 0.72 mmol) and 3-(4-Methyl-1H-imidazol-1-yl)propan-1-amine(0.10 g, 0.72 mmol) as described above.

Yield: 0.045 g (20.3%). ¹H NMR (DMSO-d₆): δ 1.86-1.93 (m, 2H); 3.03 (s,3H); 3.14-3.19 (m, 2H); 3.86-3.90 (m, 2H); 6.82 (s, H); 7.34-7.36 (m,2H); 7.44 (s, H); 7.73-7.76 (m, 3H); 9.41 (s, H). MS m/z 308.4 (M+H)⁺;HPLC (λ=214 nm, [C]): rt 8.13 min (100%)

Example 27(3,4-dichlorophenyl)-2-cyano-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine

The compound was synthesized starting from1,2-dichloro-4-isothiocyanatobenzene (0.147 g, 0.72 mmol) and3-(4-Methyl-1H-imidazol-1-yl)propan-1-amine (0.10 g, 0.72 mmol) asdescribed above.

Yield: 0.070 g (27.6%). ¹H NMR (DMSO-d₆): δ 1.84-1.91 (m, 2H); 2.03 (s,3H); 3.10-3.15 (m, 2H); 3.84-3.88 (m, 2H); 6.81 (s, H); 7.19-7.22 (m,H); 7.43-7.50 (br m, 3H); 7.54-7.56 (m, H); 9.14 (s, H). MS m/z 351.3(M+H)⁺; HPLC (λ=214 nm, [C]): rt 12.85 min (100%)

Example 282-cyano(4-methoxyphenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)-guanidine

The compound was synthesized starting from1-isothiocyanato-4-methoxybenzene (0.119 g, 0.72 mmol) and3-(4-Methyl-1H-imidazol-1-yl)propan-1-amine (0.10 g, 0.72 mmol) asdescribed above.

Yield: 0.090 g (40.0%). ¹H NMR (CDCl₃): δ 1.92-1.98 (m, 2H); 2.14 (s,3H); 3.19-3.24 (m, 2H); 3.80 (s, 3H); 3.83-3.87 (m, 2H); 4.73 (br s, H);6.54 (s, H); 6.91-6.94 (m, 2H); 7.07-7.11 (m, 2H), 7.23-7.29 (m, 2H). MSm/z 313.2 (M+H)⁺; HPLC (λ=214 nm, [C]): rt 8.35 min (100%)

Example 292-cyano-1-[3-(4-methyl-1H-imidazol-1-yl)propyl]-4-phenylbenzene-1-guanidine

The compound was synthesized starting from1-isothiocyanato-4-phenylbenzene (0.380 g, 1.18 mmol) and3-(4-Methyl-1H-imidazol-1-yl)propan-1-amine (0.164 g, 1.18 mmol) asdescribed above.

Yield: 0.25 g (59.1%). ¹H NMR (DMSO-d₆, 500 MHz): δ 1.89-1.95 (m, 2H);2.06 (s, 3H); 3.16-3.19 (m, 2H); 3.89-3.92 (m, 2H); 6.85 (s, H);7.31-7.36 (br m, 4H); 7.43-7.48 (br m, 3H); 7.64-7.66 (m, 4H); 9.08 (brs, H). MS m/z 359.4 (M+H)⁺; HPLC (λ=214 nm, [C]): rt 14.19 min (99.3%)

Example 302-cyano(3-(4-methyl-1H-imidazol-1-yl)propyl)-3-(naphthalen-2-yl)-guanidine

The compound was synthesized starting from 2-isothiocyanatonaphthalene(0.167 g, 0.90 mmol) and 3-(4-Methyl-1H-imidazol-1-yl)propan-1-amine(0.125 g, 0.90 mmol) as described above.

Yield: 0.093 g (31.1%). ¹H NMR (DMSO-d₆, 500 MHz): δ 1.89-1.95 (m, 2H);2.06 (s, 3H); 3.16-3.20 (m, 2H); 3.90-3.93 (m, 2H); 6.87 (s, H);7.31-7.33 (m, H); 7.38-7.40 (m, H); 7.44-7.57 (br m, 3H); 7.70 (s, H);7.84-7.90 (br m, 3H); 9.21 (br s, H). MS m/z 333.5 (M+H)⁺; HPLC (λ=214nm, [C]): rt 11.73 min (97.14%)

Activity Screening

Fluorometric Assays

All measurements were performed with a BioAssay Reader HTS-7000Plus formicroplates (Perkin Elmer) at 30° C. QC activity was evaluatedfluorometrically using H-Gln-βNA. The samples consisted of 0.2 mMfluorogenic substrate, 0.25 U pyroglutamyl aminopeptidase (Unizyme,Hørsholm, Denmark) in 0.2 M Tris/HCl, pH 8.0 containing 20 mM EDTA andan appropriately diluted aliquot of QC in a final volume of 250 μl.Excitation/emission wavelengths were 320/410 nm. The assay reactionswere initiated by addition of glutaminyl cyclase. QC activity wasdetermined from a standard curve of β-naphthylamine under assayconditions. One unit is defined as the amount of QC catalyzing theformation of 1 μmol pGlu-MNA from H-Gln-βNA per minute under thedescribed conditions.

In a second fluorometric assay, QC was activity determined usingH-Gln-AMC as substrate. Reactions were carried out at 30° C. utilizingthe NOVOStar reader for microplates (BMG labtechnologies). The samplesconsisted of varying concentrations of the fluorogenic substrate, 0.1 Upyroglutamyl aminopeptidase (Qiagen) in 0.05 M Tris/HCl, pH 8.0containing 5 mM EDTA and an appropriately diluted aliquot of QC in afinal volume of 250 μl. Excitation/emission wavelengths were 380/460 nm.The assay reactions were initiated by addition of glutaminyl cyclase. QCactivity was determined from a standard curve of7-amino-4-methylcoumarin under assay conditions. The kinetic data wereevaluated using GraFit sofware.

Spectrophotometric Assay of QC

This novel assay was used to determine the kinetic parameters for mostof the QC substrates. QC activity was analyzed spectrophotometricallyusing a continuous method, that was derived by adapting a previousdiscontinuous assay (Bateman, R. C. J. 1989 J Neurosci Methods 30,23-28) utilizing glutamate dehydrogenase as auxiliary enzyme. Samplesconsisted of the respective QC substrate, 0.3 mM NADH, 14 mMα-Ketoglutaric acid and 30 U/ml glutamate dehydrogenase in a finalvolume of 250 μl. Reactions were started by addition of QC and persuedby monitoring of the decrease in absorbance at 340 nm for 8-15 min.

The initial velocities were evaluated and the enzymatic activity wasdetermined from a standard curve of ammonia under assay conditions. Allsamples were measured at 30° C., using either the SPECTRAFluor Plus orthe Sunrise (both from TECAN) reader for microplates. Kinetic data wasevaluated using GraFit software.

Inhibitor Assay

For inhibitor testing, the sample composition was the same as describedabove, except of the putative inhibitory compound added. For a rapidtest of QC-inhibition, samples contained 4 mM of the respectiveinhibitor and a substrate concentration at 1 K_(M). For detailedinvestigations of the inhibition and determination of K_(i)-values,influence of the inhibitor on the auxiliary enzymes was investigatedfirst. In every case, there was no influence on either enzyme detected,thus enabling the reliable determination of the QC inhibition. Theinhibitory constant was evaluated by fitting the set of progress curvesto the general equation for competitive inhibition using GraFitsoftware.

Analytical Methods

The analytical HPLC-system consisted of a Merck-Hitachi device (modelLaChrom®) utilizing a Li-Chrospher® 100 RP 18 (5 μm), analytical column(length: 125 mm, diameter: 4 mm), and a diode array detector (DAD) withλ=214 nm as the reporting wavelength. The compounds were analyzed usinga gradient at a flow rate of 1 mL/min; whereby eluent (A) wasacetonitrile, eluent (B) was water, both containing 0.1% (v/v) trifluoroacetic acid applying the following gradient: Method [A]: 0 min-5 min→5%(A), 5 min-17 min→5-15% (A), 15 min-27 min→15-95% (A) 27 min-30 min→95%(A). Method [B]: 0 min-15 min→5-50% (A), 15 min-20 min→50-95% (A), 20min-23 min→95% (A). Method [C]: 0 min-20 min→5-60% (A), 20 min-25min→60-95% (A), 25 min-30 min→95% (A). The purities of all reportedcompounds were determined by the percentage of the peak area at 214 nm.

ESI-Mass spectra were obtained with a SCIEX API 365 spectrometer (PerkinElmer) utilizing the positive ionization mode.

The high resolution positive ion ESI mass spectra were obtained from aBruker Apex III 70e Fourier transform ion cyclotron resonance massspectrometer (Bruker Daltonics, Billerica, USA) equipped with anInfinity™ cell, a 7.0 Tesla superconducting magnet (Bruker, Karlsruhe,Germany), an RF-only hexapole ion guide and an external electrospray ionsource (API Apollo, voltages: endplate, −3.700V; capillary, −4.400V;capillary exit, 100V; skimmer 1.15 V; skimmer 2.6 V). Nitrogen was usedas drying gas at 150° C. The sample solutions were introducedcontinuously via a syringe pump with a flow rate of 120 μl h⁻¹. All datawere acquired with 256 k data points and zero filled to 1024 k byaveraging 32 scans.

The melting points were detected utilizing a Kofler melting pointdevice. They are not corrected The ¹H NMR-Spectra (500 MHz) wererecorded at a BRUKER AC 500. The solvent was DMSO-D₆, unless otherwisespecified. Chemical shifts are expressed as parts per million (ppm)downfiled from tetramethylsilan. Splitting patterns have been designatedas follows: s (singulet), d (doublet), dd (doublet of doublet), t(triplet), m (multiplet) and br (broad signal).

MALDI-TOF Mass Spectrometry

Matrix-assisted laser desorption/ionization mass spectrometry wascarried out using the Hewlett-Packard G2025 LD-TOF System with a lineartime of flight analyzer. The instrument was equipped with a 337 nmnitrogen laser, a potential acceleration source (5 kV) and a 1.0 mflight tube. Detector operation was in the positive-ion mode and signalsare recorded and filtered using LeCroy 9350M digital storageoscilloscope linked to a personal computer. Samples (5 μl) were mixedwith equal volumes of the matrix solution. For matrix solution DHAP/DAHCwas used, prepared by solving 30 mg 2′,6′-dihydroxyacetophenone(Aldrich) and 44 mg diammonium hydrogen citrate (Fluka) in 1 mlacetonitrile/0.1% TFA in water (1/1, v/v). A small volume (≈1 μl) of thematrix-analyte-mixture was transferred to a probe tip and immediatelyevaporated in a vacuum chamber (Hewlett-Packard G2024A sample prepaccessory) to ensure rapid and homogeneous sample crystallization.

For long-term testing of Glu¹-cyclization, Aβ-derived peptides wereincubated in 100 μl 0.1 M sodium acetate buffer, pH 5.2 or 0.1 MBis-Tris buffer, pH 6.5 at 30° C. Peptides were applied in 0.5 mM[Aβ(3-11)a] or 0.15 mM [Aβ(3-21)a] concentrations, and 0.2 U QC is addedall 24 hours. In case of Aβ(3-21)a, the assays contained 1% DMSO. Atdifferent times, samples are removed from the assay tube, peptidesextracted using ZipTips (Millipore) according to the manufacturer'srecommendations, mixed with matrix solution (1:1 v/v) and subsequentlythe mass spectra recorded. Negative controls either contain no QC orheat deactivated enzyme. For the inhibitor studies the samplecomposition was the same as described above, with exception of theinhibitory compound added (5 mM or 2 mM of a test compound of theinvention).

The first QC inhibitors were disclosed in WO 2004/098591 and WO2005/075436. There are no other potent QC inhibitors known in the art.The same holds true for combinations and compositions for the treatmentof neuronal diseases comprising QC inhibitors. Compounds andcombinations of the invention may have the advantage that they are, forexample, more potent, more selective, have fewer side-effects, havebetter formulation and stability properties, have better pharmacokineticproperties, be more bioavailable, be able to cross blood brain barrierand are more effective in the brain of mammals, are more compatible oreffective in combination with other drugs or be more readily synthesizedthan other compounds of the prior art.

Throughout the specification and the claims which follow, unless thecontext requires otherwise, the word ‘comprise’, and variations such as‘comprises’ and ‘comprising’, will be understood to imply the inclusionof a stated integer, step, group of integers or group of steps but notto the exclusion of any other integer, step, group of integers or groupof steps.

All publications, patents, patent applications, and other referencescited in this application are incorporated herein by reference in theirentirety for all purposes to the same extent as if each individualpublication, patent, patent application or other reference wasspecifically and individually indicated to be incorporated by referencein its entirety for all purposes. Citation of a reference herein shallnot be construed as an admission that such is prior art to the presentinvention.

The invention embraces all combinations of preferred and more preferredgroups and embodiments of groups recited above.

1. A compound of formula (I),

or a pharmaceutically acceptable salt thereof, including all tautomersand stereoisomers thereof wherein: R¹ represents alkyl; alkenyl, whereinthe double bond is not adjacent to the nitrogen; carbocyclyl;—C₁₋₆alkyl-carbocyclyl; heterocyclyl; —C₁₋₆alkyl-heterocyclyl; aryl;heteroaryl; —C₁₋₆alkylaryl; —C₁₋₆alkylheteroaryl; -phenyl fused tocarbocyclyl or -phenyl fused to heterocyclyl; in which any of theaforesaid carbocyclyl and heterocyclyl groups may optionally besubstituted by one or more groups selected from methyl and oxo; and inwhich any of the aforesaid phenyl, aryl and heteroaryl groups mayoptionally be substituted by one or more substituents selected fromC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, —C₁₋₆thioalkyl,—SO₂C₁₋₄alkyl, C₁₋₆alkoxy-, —O—C₃₋₈cycloalkyl, C₃₋₈cycloalkyl,—SO₂C₃₋₈cycloalkyl, C₃₋₆alkenyloxy-, C₃₋₆alkynyloxy-, —C(O)C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)OH, —NH₂,—NHC₁₋₄alkyl, —N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl),—C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)OC₁₋₆alkyl, —SOC₁₋₄alkyl and—SOC₃₋₆cycloalkyl; or R¹ represents phenyl substituted by phenyl, orphenyl substituted by an optionally substituted monocyclic heteroarylgroup in which any of the aforesaid phenyl and monocyclic heteroarylgroups may optionally be substituted by one or more groups selected fromC₁₋₄alkyl, halogen and C₁₋₄alkoxy; or R¹ represents phenyl substitutedby benzyloxy- in which any of the aforesaid phenyl or benzyloxy groupsmay optionally be substituted on the ring by one or more groups selectedfrom C₁₋₄alkyl, halogen and C₁₋₄alkoxy; X represents C or N; and Arepresents

wherein Y represents a C₂₋₅ alkylene chain, which may optionally besubstituted by one or two methyl groups or may optionally be substitutedby two alkylene substituents at the same position wherein the twoalkylene substituents are joined to each other to form aC₃₋₅spiro-cycloalkyl group and R², R³ and R⁴ independently represent Hor C₁₋₂alkyl, provided that R² and R³ and R⁴ do not all represent H; orA represents

wherein Z represents a bond, —CH₂—, —CH₂—CH₂—, —CH(Me)—, —CH(Me)—CH₂— or—CH₂—CH(Me)— and R⁵ and R⁶ independently represent H or C₁₋₂alkyl and Brepresents H or methyl.
 2. A compound according to claim 1 wherein R¹represents alkyl; alkenyl, wherein the double bond is not adjacent tothe nitrogen; carbocyclyl; —C₁₋₆alkyl-carbocyclyl; heterocyclyl;—C₁₋₆alkyl-heterocyclyl; aryl; heteroaryl; —C₁₋₆alkylaryl;—C₁₋₆alkylheteroaryl; -phenyl fused to carbocyclyl or -phenyl fused toheterocyclyl; in which any of the aforesaid carbocyclyl and heterocyclylgroups may optionally be substituted by one or more groups selected frommethyl and oxo; and in which any of the aforesaid phenyl, aryl andheteroaryl groups may optionally be substituted by one or moresubstituents selected from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, —C₁₋₆thioalkyl, —SO₂C₁₋₄alkyl, C₁₋₆alkoxy-,—O—C₃₋₈cycloalkyl, C₃₋₈cycloalkyl, —SO₂C₃₋₈cycloalkyl, C₃₋₆alkenyloxy-,C₃₋₆alkynyloxy-, —C(O)C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl-, nitro, halogen,cyano, hydroxyl, —C(O)OH, —NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)(C₁₋₄alkyl),—C(O)N(C₁₋₄alkyl)(C₁₋₄alkyl), —C(O)NH₂ and —C(O)NH(C₁₋₄alkyl); or R¹represents phenyl substituted by phenyl, or phenyl substituted by anoptionally substituted monocyclic heteroaryl group in which any of theaforesaid phenyl and monocyclic heteroaryl groups may optionally besubstituted by one or more groups selected from C₁₋₄alkyl, halogen andC₁₋₄alkoxy.
 3. A compound according to claim 1 wherein R¹ representsaryl; heteroaryl; -phenyl fused to carbocyclyl; phenyl fused toheterocyclyl; or R¹ represents phenyl substituted by phenyl, or phenylsubstituted by a monocyclic heteroaryl group; in which any ofaforementioned aryl, phenyl, heteroaryl, carbocyclyl and heterocyclylmay optionally be substituted.
 4. A compound according to claim 1wherein R¹ represents optionally substituted aryl.
 5. A compoundaccording to claim 4 wherein R¹ is phenyl substituted by one, two orthree substituents selected from C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl,halogen and cyano.
 6. A compound according to claim 4 wherein R¹represents unsubstituted aryl selected from phenyl, naphthalen-1-yl andnaphthalen-2-yl.
 7. A compound according to claim 3 wherein R¹represents optionally substituted phenyl fused to optionally substitutedheterocyclyl.
 8. A compound according to claim 3 wherein R¹ representsoptionally substituted heteroaryl.
 9. A compound according to claim 1wherein A represents

wherein Y, R³ and R⁴ are as defined in claim
 1. 10. A compound accordingto claim 9 wherein R² represents H, R³ represents H and R⁴ representsmethyl.
 11. A compound according to claim 9 wherein Y represents anunsubstituted C₂₋₅ alkylene chain.
 12. A compound according to claim 11wherein Y represents —(CH₂)₃— or —(CH₂)₄—.
 13. A compound according toclaim 12 wherein A represents


14. A compound according to claim 1 wherein A represents

wherein R⁵, R⁶ and Z are as defined in claim
 1. 15. A compound accordingto claim 14 wherein R⁵ represents H and R⁶ represents H.
 16. A compoundaccording to claim 14 wherein Z represents a bond, —CH₂— or —CH₂—CH₂—.17. A compound according to claim 1 wherein B represents H.
 18. Acompound according to claim 1 as defined in any one of examples 1 to 30:(1)2-cyano(4-ethylphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine,(2)2-cyano(4-isopropylphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine,(3)2-cyano(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine,(4)2-cyano(4-cyanophenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine,(5)2-cyano(3,4,5-trimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine,(6)2-cyano(4-ethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine,(7)2-cyano(3-(5-methyl-1H-imidazol-1-yl)propyl)-3-(3,4-dimethylphenyl)guanidine,(8) (3-(5-methyl-1H-imidazol-1-yl)propyl)-2-cyano-3-mesitylguanidine,(9)(3-(5-methyl-1H-imidazol-1-yl)propyl)-2-cyano-3-(biphenyl-4-yl)guanidine,(10)(3-(5-methyl-1H-imidazol-1-yl)propyl)-2-cyano-3-(naphthalen-2-yl)guanidine,(11)(3-(5-methyl-1H-imidazol-1-yl)propyl)-2-cyano-3-(naphthalen-1-yl)guanidine,(12)(3-(5-methyl-1H-imidazol-1-yl)propyl)-3-(benzo[c][1,2,5]thiadiazol-6-yl)-2-cyanoguanidine,(13)(3-(5-methyl-1H-imidazol-1-yl)propyl)-3-(3,4-dichlorophenyl)-2-cyanoguanidine,(14)(benzo[d][1,3]dioxol-6-yl)-2-cyano-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine,(15)2-cyano(4-methoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine,(16)2-cyano(3,5-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)guanidine,(17)2-cyano(4-ethoxyphenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine(18)2-cyano(3,5-dimethoxyphenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine(19)2-cyano(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine(20) 2-cyano(mesityl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine(21)2-cyano(4-isopropylphenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine(22)2-cyano(4-ethylphenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine(23)2-cyano(3-(4-methyl-1H-imidazol-1-yl)propyl)-3-(naphthalen-1-yl)guanidine(24)(benzo[c][1,2,5]thiadiazol-6-yl)-2-cyano-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine(25)2-cyano(3,4,5-trimethoxyphenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine(26)2-cyano(4-cyanophenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine(27)(3,4-dichlorophenyl)-2-cyano-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine(28)2-cyano(4-methoxyphenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)guanidine(29)2-cyano-1-[3-(4-methyl-1H-imidazol-1-yl)propyl]-4-phenylbenzene-1-guanidine(30)2-cyano(3-(4-methyl-1H-imidazol-1-yl)propyl)-3-(naphthalen-2-yl)guanidineor a pharmaceutically acceptable salt, solvate or polymorph of any onethereof.
 19. A pharmaceutical composition comprising a compoundaccording to claim 1 optionally in combination with one or moretherapeutically acceptable diluents or carriers.
 20. The pharmaceuticalcomposition of claim 19, which comprises additionally at least onecompound, selected from the group consisting of neuroprotectants,antiparkinsonian drugs, amyloid protein deposition inhibitors, betaamyloid synthesis inhibitors, antidepressants, anxiolytic drugs,antipsychotic drugs and anti-multiple sclerosis drugs.
 21. Thepharmaceutical composition of claim 19 which comprises additionally atleast one compound, selected from the group consisting ofPEP-inhibitors, LiCl, inhibitors of inhibitors of DP IV or DP IV-likeenzymes, acetylcholinesterase (ACE) inhibitors, PIMT enhancers,inhibitors of beta secretases, inhibitors of gamma secretases,inhibitors of neutral endopeptidase, inhibitors of Phosphodiesterase-4(PDE-4), TNFalpha inhibitors, muscarinic M1 receptor antagonists, NMDAreceptor antagonists, sigma-1 receptor inhibitors, histamine H3antagonists, immunomodulatory agents, immunosuppressive agents or anagent selected from the group consisting of antegren (natalizumab),Neurelan (fampridine-SR), campath (alemtuzumab), IR 208, NBI 5788/MSP771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD271, adapalene), BAY 361677 (interleukin-4),matrix-metalloproteinase-inhibitors, interferon-tau (trophoblastin) andSAIK-MS.
 22. A process for preparation of a compound of formula (I)according to claim 1, which comprises reaction of a compound of formula(II)

with a compound of formula (III)

wherein R¹, A and B are as defined in claim
 1. 23. A process forpreparation of a compound of formula (I) according to claim 1, whichcomprises reaction of a compound of formula (VI)

wherein R⁷ represents C₁₋₆alkyl and R¹ is as defined in claim 1; and Xrepresents C or N; with a compound of formula (III)

wherein A and B are as defined in claim
 1. 24. The pharmaceuticalcomposition of claim 19 which comprises additionally at least onecompound, selected from the group consisting of PEPinhibitors, LiCI,inhibitors of inhibitors of DP IV or DP IV-like enzymes,acetylcholinesterase (ACE) inhibitors, PIMT enhancers, inhibitors ofbeta secretases, inhibitors of gamma secretases, inhibitors of neutralendopeptidase, inhibitors of Phosphodiesterase-4 (PDE-4), TNFalphainhibitors, muscarinic M1 receptor antagonists, NMDA receptorantagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, oran agent selected from the group consisting of antegren (natalizumab),Neurelan (fampridine-SR), campath (alemtuzumab), IR 208, NBI 5788/MSP771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD271, adapalene), BAY 361677 (interleukin-4),matrix-metalloproteinase-inhibitors, interferon-tau (trophoblastin) andSAIK-MS.